Retinoblastoma protein: Difference between revisions

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{{redirect|RB1|the automobile|Red Bull RB1}}
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{{Infobox_gene}}
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The '''retinoblastoma protein''' (protein name abbreviated '''pRb'''; gene name abbreviated '''''RB''''' or '''''RB1''''') is a [[tumor suppressor]] [[protein]] that is dysfunctional in several major [[cancers]].<ref name="Murphree1984">{{cite journal | vauthors = Murphree AL, Benedict WF | title = Retinoblastoma: clues to human oncogenesis | journal = Science | volume = 223 | issue = 4640 | pages = 1028–33 | date = March 1984 | pmid = 6320372 | doi = 10.1126/science.6320372 }}</ref> One function of pRb is to prevent excessive [[cell (biology)|cell]] growth by inhibiting [[cell cycle]] progression until a cell is ready to divide. When the cell is ready to divide, pRb is phosphorylated, becomes inactive and allows cell cycle progression.  It is also a recruiter of several [[chromatin remodeling]] enzymes such as methylases and acetylases.<ref name="pmid7838522">{{cite journal |vauthors = Shao Z, Robbins PD |title=Differential regulation of E2F and Sp1-mediated transcription by G1 cyclins |journal=Oncogene |volume=10 |issue=2 |pages=221–8 |year=1995 |pmid=7838522 }}</ref>
| require_manual_inspection = no
| update_protein_box = yes
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{GNF_Protein_box
| image = PBB_Protein_RB1_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1ad6.
| PDB = {{PDB2|1ad6}}, {{PDB2|1gh6}}, {{PDB2|1gux}}, {{PDB2|1o9k}}, {{PDB2|2aze}}
| Name = Retinoblastoma 1 (including osteosarcoma)
| HGNCid = 9884
| Symbol = RB1
| AltSymbols =; OSRC; RB
| OMIM = 180200
| ECnumber =
| Homologene = 272
| MGIid = 97874
| GeneAtlas_image1 = PBB_GE_RB1_203132_at.png
| GeneAtlas_image2 = PBB_GE_RB1_211540_s_at.png
<!-- The Following entry is a time stamp of the last bot update.  It is typically hidden data -->
| DateOfBotUpdate = 00:24, 15 September 2007 (UTC)
| Function = {{GNF_GO|id=GO:0003674 |text = molecular_function}} {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0003713 |text = transcription coactivator activity}} {{GNF_GO|id=GO:0008134 |text = transcription factor binding}} {{GNF_GO|id=GO:0016564 |text = transcription repressor activity}} {{GNF_GO|id=GO:0019900 |text = kinase binding}} {{GNF_GO|id=GO:0050681 |text = androgen receptor binding}}
| Component = {{GNF_GO|id=GO:0000785 |text = chromatin}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005667 |text = transcription factor complex}} {{GNF_GO|id=GO:0005819 |text = spindle}}
| Process = {{GNF_GO|id=GO:0000075 |text = cell cycle checkpoint}} {{GNF_GO|id=GO:0000082 |text = G1/S transition of mitotic cell cycle}} {{GNF_GO|id=GO:0000122 |text = negative regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0000279 |text = M phase}} {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006469 |text = negative regulation of protein kinase activity}} {{GNF_GO|id=GO:0007049 |text = cell cycle}} {{GNF_GO|id=GO:0007050 |text = cell cycle arrest}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0030308 |text = negative regulation of cell growth}} {{GNF_GO|id=GO:0030521 |text = androgen receptor signaling pathway}} {{GNF_GO|id=GO:0043550 |text = regulation of lipid kinase activity}} {{GNF_GO|id=GO:0045944 |text = positive regulation of transcription from RNA polymerase II promoter}} {{GNF_GO|id=GO:0051146 |text = striated muscle cell differentiation}} {{GNF_GO|id=GO:0051301 |text = cell division}} {{GNF_GO|id=GO:0051318 |text = G1 phase}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 5925
    | Hs_Ensembl = ENSG00000139687
    | Hs_RefseqProtein = NP_000312
    | Hs_RefseqmRNA = NM_000321
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 13
    | Hs_GenLoc_start = 47775912
    | Hs_GenLoc_end = 47954123
    | Hs_Uniprot = P06400
    | Mm_EntrezGene = 19645
    | Mm_Ensembl = ENSMUSG00000022105
    | Mm_RefseqmRNA = NM_009029
    | Mm_RefseqProtein = NP_033055
    | Mm_GenLoc_db =
    | Mm_GenLoc_chr = 14
    | Mm_GenLoc_start = 71929657
    | Mm_GenLoc_end = 72059946
    | Mm_Uniprot = Q3UFM7
  }}
}}


==Overview==
Rb belongs to the [[pocket protein family]], whose members have a pocket for the functional binding of other proteins.<ref name="Korenjak and Brehm">{{cite journal | vauthors = Korenjak M, Brehm A | title = E2F-Rb complexes regulating transcription of genes important for differentiation and development | journal = Current Opinion in Genetics & Development | volume = 15 | issue = 5 | pages = 520–7 | date = October 2005 | pmid = 16081278 | doi = 10.1016/j.gde.2005.07.001 | url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VS0-4GSJXD8-1&_coverDate=10%2F31%2F2005&_alid=324524977&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=6248&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=433dbaa00425e7b5ca02f73279fbc321 }}</ref><ref name="Münger and Howley">{{cite journal | vauthors = Münger K, Howley PM | title = Human papillomavirus immortalization and transformation functions | journal = Virus Res. | volume = 89 | issue = 2 | pages = 213–28 | date = November 2002 | pmid = 12445661 | doi = 10.1016/S0168-1702(02)00190-9 | url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T32-46W13SB-2&_coverDate=11%2F30%2F2002&_alid=324525784&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4934&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=e7d4057a8f6b3c57fee07e374e77fd5d }}</ref> Should an [[oncogenic]] protein, such as those produced by cells infected by high-risk types of [[human papillomavirus]]es, bind and inactivate pRb, this can lead to cancer. The RB gene may have been responsible for the evolution of multicellularity in several lineages of life including animals.<ref>https://futurism.com/multicellular-life-caused-one-gene-gene-suppresses-cancer/</ref>
The '''retinoblastoma protein''', also called '''pRb''' or '''''Rb''''', is a [[tumor suppressor gene|tumor suppressor]] [[protein]] found to be dysfunctional in a number of types of [[cancer]].<ref name="Murphree1984">Murphree A.L. and Benedict W.F. 1984. Retinoblastoma: clues to human oncogenesis in ''[[Science (journal)|Science]]'', 223(4640): 1028-1033. {{Entrez Pubmed|6320372}} Retrieved on January 24, 2007.</ref> pRb was so named because [[retinoblastoma]] cancer results when the protein is inactivated by a mutation in both [[allele]]s of the [[RB1]] gene that [[code for|codes for]] it. The "p" in pRb stands for protein and is a way to distinguish it from the gene, ''Rb''.  pRb is usually present as a [[phosphoprotein]] inside cells and is a target for [[phosphorylation]] by several [[kinase]]s as described [[#Activation and inactivation|below]]. One highly studied function of pRb is to prevent the [[cell (biology)|cell]] from dividing or progressing through the [[cell cycle]].  Thus, when pRb is ineffective at this role, [[mutation|mutated]] cells can continue to divide and may become cancerous.


pRb is a member of the '[[Pocket protein family]]', because it has a pocket to which proteins can bind.<ref name="Korenjak and Brehm">Korenjak M. and Brehm A.  2005.  [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VS0-4GSJXD8-1&_coverDate=10%2F31%2F2005&_alid=324524977&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=6248&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=433dbaa00425e7b5ca02f73279fbc321 E2F–Rb complexes regulating transcription of genes important for differentiation and development].  ''Current Opinion in Genetics & Development'', 15(5): 520-527.</ref><ref name="Münger and Howley">Münger K. and Howley P.M.  2002. [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T32-46W13SB-2&_coverDate=11%2F30%2F2002&_alid=324525784&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4934&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=e7d4057a8f6b3c57fee07e374e77fd5d Human papillomavirus immortalization and transformation functions]. ''Virus Research'', 89: 213–228. </ref>  [[Oncogenic]] proteins such as those produced by cells infected by high-risk types of [[human papillomavirus]]es can bind and inactivate pRb, which can lead to cancer.
== Name and genetics ==


==Cell cycle suppression==
In humans, the protein is encoded by the RB1 gene located on chromosome 13—more specifically, [[Chromosome 13 (human)|13q14.1-q14.2]]. If both [[allele]]s of this gene are mutated early in life, the protein is inactivated and results in development of [[retinoblastoma]] cancer, hence the name ''Rb''. Retinal cells are not sloughed off or replaced, and are subjected to high levels of mutagenic UV radiation, and thus most pRB knock-outs occur in retinal tissue (but it's also been documented in certain skin cancers in patients from New Zealand where the amount of UV radiation is significantly higher).
pRb prevents the cell from replicating damaged DNA by preventing its progression through the cell cycle into its S, or [[synthesis phase]] or progressing through G1, or [[first gap phase]].<ref name="Das">Das S.K., Hashimoto T., Shimizu K., Yoshida T., Sakai T., Sowa Y., Komoto A., and Kanazawa K.  2005.  Fucoxanthin induces cell cycle arrest at G0/G1 phase in human colon carcinoma cells through up-regulation of p21WAF1/Cip1. ''Biochimica et Biophysica Acta'', 1726(3):328-335. PMID 16236452. Retrieved on January 24, 2007.</ref>  pRb binds and inhibits [[transcription factor]]s of the [[E2F]] family. E2F transcription factors are dimers of an E2F protein and a DP protein.<ref name="Wu1995"> Wu C.L., Zukerberg L.R., Ngwu C., Harlow E. and Lees J.A. 1995. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=7739537 ''In vivo'' association of E2F and DP family proteins.] ''Molecular and Cellular Biology'' 15(5): 2536-2546. {{Entrez Pubmed|7739537}} Retrieved on January 24, 2007.</ref> The [[Transcription (genetics)|transcription]] activating complexes of E2 promoter-binding–protein-dimerization partners (E2F-DP) can push a cell into S phase.<ref name="Funk">Funk J.O., Waga S., Harry J.B., Espling E., Stillman B., and Galloway D.A.  1997.  [http://www.genesdev.org/cgi/content/full/11/16/2090 Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein]. ''Trends in Genetics'', 13(12): 474.</ref><ref name="De Veylder">De Veylder L., Joubès J., and Inzé D. 2003. [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VS4-49KH3G2-1&_coverDate=12%2F31%2F2003&_alid=324521740&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=6252&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=40e5304bd36a43ee0f9ef82ab574339d Plant cell cycle transitions]. ''Current Opinion in Plant Biology''. 6(6): 536-543.  </ref><ref name="de Jager">de Jager S.M., Maughan S., Dewitte W., Scofield S., and Murray J.A.H.  2005.  [http://www.biot.cam.ac.uk/jahm/pdf_files/SCDB385.pdf The developmental context of cell-cycle control in plants]. ''Seminars in Cell & Developmental Biology''. 16(3): 385-396. PMID 15840447. Retrieved on January 24, 2007.</ref><ref name="Greenblatt">Greenblatt R.J.  2005.  [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T5D-4H6P7Y9-1&_user=10&_handle=V-WA-A-W-W-MsSAYZA-UUA-U-AABAVZDCWU-AAWEUVYBWU-BEAYVEYEY-W-U&_fmt=summary&_coverDate=09%2F15%2F2005&_rdoc=1&_orig=browse&_srch=%23toc%235000%232005%23999729981%23607092!&_cdi=5000&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=42b5289fd6b206fd7ae9269741210c39 Human papillomaviruses: Diseases, diagnosis, and a possible vaccine]. ''Clinical Microbiology Newsletter'', 27(18): 139-145. doi:10.1016/j.clinmicnews.2005.09.001. Retrieved on January 24, 2007. </ref><ref name="Sinal and Woods">Sinal S.H. and Woods C.R.  2005.  [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16210110&query_hl=8 Human papillomavirus infections of the genital and respiratory tracts in young children].  ''Seminars in Pediatric Infectious Diseases'', 16(4): 306-316. PMID 16210110. Retrieved on January 24, 2007.</ref> As long as E2F-DP is inactivated, the cell remains stalled in the G1 phase.  When pRb is bound to E2F, the complex acts as a growth suppressor and prevents progression through the cell cycle.<ref name="Münger and Howley"/>  The pRb-E2F/DP complex also attracts a [[histone deacetylase]] (HDAC) protein to the [[chromatin]], further suppressing [[DNA synthesis]].


==Activation and inactivation==
Two forms of retinoblastoma were noticed: a bilateral, familial form and a unilateral, sporadic form. Sufferers of the former were 6 times more likely to develop other types of cancer later in life.<ref>{{cite journal | vauthors = Kleinerman RA, Tucker MA, Tarone RE, Abramson DH, Seddon JM, Stovall M, Li FP, Fraumeni JF | title = Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up | journal = J. Clin. Oncol. | volume = 23 | issue = 10 | pages = 2272–9 | date = April 2005 | pmid = 15800318 | doi = 10.1200/JCO.2005.05.054 }}</ref> This highlighted the fact that mutated Rb could be inherited and lent support to the [[two-hit hypothesis]]. This states that only one working allele of a tumour suppressor gene is necessary for its function (the mutated gene is recessive), and so both need to be mutated before the cancer phenotype will appear. In the familial form, a mutated allele is inherited along with a normal allele. In this case, should a cell sustain only ''one'' mutation in the other RB gene, all Rb in that cell would be ineffective at inhibiting cell cycle progression, allowing cells to divide uncontrollably and eventually become cancerous. Furthermore, as one allele is already mutated in all other somatic cells, the future incidence of cancers in these individuals is observed with [[Linear function|linear]] kinetics.<ref>{{cite journal | vauthors = Knudson AG | title = Mutation and Cancer: Statistical Study of Retinoblastoma | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 68 | issue = 4 | pages = 820–3 | date = April 1971 | pmid = 5279523 | pmc = 389051 | doi = 10.1073/pnas.68.4.820 }}</ref> The working allele need not undergo a mutation ''per se'', as [[loss of heterozygosity]] (LOH) is frequently observed in such tumours.


pRb can actively inhibit cell cycle progression when it is [[phosphorylation|dephosphorylated]] while this function is inactivated when pRb is phosphorylated. pRb is activated near the end of G1 phase when a [[phosphatase]] dephosphorylates it, allowing it to bind E2F.<ref name="Münger and Howley"/><ref name="Vietri2006">Vietri M., Bianchi M., Ludlow J.W., Mittnacht S. and Villa-Moruzzi E. 2006. [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16466572 Direct interaction between the catalytic subunit of Protein Phosphatase 1 and pRb.] ''Cancer cell international'', 6(3): 3 {{Entrez Pubmed|16466572}} Retrieved on January 24, 2007.</ref>
However, in the sporadic form, both alleles would need to sustain a mutation before the cell can become cancerous. This explains why sufferers of sporadic retinoblastoma are not at increased risk of cancers later in life, as both alleles are functional in all their other cells. Future cancer incidence in sporadic Rb cases is observed with [[polynomial]] kinetics, not exactly [[quadratic function|quadratic]] as expected because the first mutation must arise through normal mechanisms, and then can be duplicated by LOH to result in a [[cancer stem cell|tumour progenitor]].


When it is time for a cell to enter S phase, complexes of [[cyclin-dependent kinase]]s (CDK) and [[cyclin]]s phosphorylate pRb, inhibiting its activity.<ref name="Korenjak and Brehm"/><ref name="Münger and Howley"/><ref name="Das"/><ref name="Bartkova">Bartkova J., Grøn B., Dabelsteen E., and Bartek J. 2003.  [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T4J-481FJ6W-4&_coverDate=02%2F28%2F2003&_alid=324520285&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4976&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=cefdf7198634e1b85780e1e5bb17bd00 Cell-cycle regulatory proteins in human wound healing]. ''Archives of Oral Biology'', 48(2): 125-132. PMID 12642231. Retrieved on January 24, 2007.</ref> The initial phosphorylation is performed by Cyclin D/CDK4,6 and followed by additional phosphorylation by Cyclin E/CDK2. pRb remains phosphorylated throughout S, G2 and M phases.<ref name="Münger and Howley"/>
RB1 [[orthologs]]<ref name="OrthoMaM">{{cite web | title = OrthoMaM phylogenetic marker: RB1 coding sequence | url =  http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000139687_RB1.xml }}</ref> have also been identified in most [[mammals]] for which complete genome data are available.


Phosphorylation of pRb allows E2F-DP to dissociate from pRb and become active.<ref name="Münger and Howley"/><ref name="De Veylder"/><ref name="Das"/>  When E2F is freed it activates factors like cyclins (e.g. Cyclin E and A), which push the cell through the cell cycle by activating cyclin-dependent kinases, and a molecule called proliferating cell nuclear antigen, or [[PCNA]], which speeds DNA replication and [[DNA repair|repair]] by helping to attach [[DNA polymerase|polymerase]] to DNA.<ref name="Funk"/><ref name="Das"/><ref name="Greenblatt"/>
RB/E2F-family proteins repress transcription.<ref name="pmid15126619">{{cite journal | vauthors = Frolov MV, Dyson NJ | title = Molecular mechanisms of E2F-dependent activation and RB-mediated repression | journal = J. Cell Sci. | volume = 117 | issue = Pt 11 | pages = 2173–81 | date = May 2004 | pmid = 15126619 | doi = 10.1242/jcs.01227 }}</ref>


==See also==
== Cell cycle suppression ==
 
Rb restricts the cell's ability to replicate DNA by preventing its progression from the G1 ([[first gap phase]]) to S ([[synthesis phase]]) phase of the cell division cycle.<ref name="Goodrich">{{cite journal | vauthors = Goodrich DW, Wang NP, Qian YW, Lee EY, Lee WH | title = The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle | journal = Cell | volume = 67 | issue = 2 | pages = 293–302 | date = November 1991 | pmid = 1655277 | doi = 10.1016/0092-8674(91)90181-w }}</ref>  Rb binds and inhibits [[E2 promoter-binding–protein-dimerization partner]] (E2F-DP) dimers, which are [[transcription factor]]s of the [[E2F]] family that push the cell into S phase.<ref name="Wu1995">{{cite journal | vauthors = Wu CL, Zukerberg LR, Ngwu C, Harlow E, Lees JA | title = In vivo association of E2F and DP family proteins | journal = Mol. Cell. Biol. | volume = 15 | issue = 5 | pages = 2536–46 | date = May 1995 | pmid = 7739537 | pmc = 230484 | doi=10.1128/mcb.15.5.2536}}</ref><ref name="Funk">{{cite journal |author1=Funk J.O. |author2=Waga S. |author3=Harry J.B. |author4=Espling E. |author5=Stillman B. |author6=Galloway D.A. |title=Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein |journal=Trends in Genetics |volume=13 |issue=12 |pages=474 |year=1997 |doi= 10.1016/0168-9525(97)90029-9|url=http://www.genesdev.org/cgi/content/full/11/16/2090}}</ref><ref name="De Veylder">{{cite journal | vauthors = De Veylder L, Joubès J, Inzé D | title = Plant cell cycle transitions | journal = Current Opinion in Plant Biology | volume = 6 | issue = 6 | pages = 536–43 | date = December 2003 | pmid = 14611951 | doi = 10.1016/j.pbi.2003.09.001 | url = http://www.sciencedirect.com/science/article/pii/S1369526603001043}}</ref><ref name="de Jager">{{cite journal | vauthors = de Jager SM, Maughan S, Dewitte W, Scofield S, Murray JA | title = The developmental context of cell-cycle control in plants | journal = Semin. Cell Dev. Biol. | volume = 16 | issue = 3 | pages = 385–96 | date = June 2005 | pmid = 15840447 | doi = 10.1016/j.semcdb.2005.02.004 }}</ref><ref name="Greenblatt">{{cite journal |author=Greenblatt RJ |title=Human papillomaviruses: Diseases, diagnosis, and a possible vaccine |journal=Clinical Microbiology Newsletter |volume=27 |issue=18 |pages=139–45 |year=2005 |doi=10.1016/j.clinmicnews.2005.09.001 |url=http://www.sciencedirect.com/science/article/pii/S0196439905000401}}</ref><ref name="Sinal and Woods">{{cite journal | vauthors = Sinal SH, Woods CR | title = Human papillomavirus infections of the genital and respiratory tracts in young children | journal = Semin Pediatr Infect Dis | volume = 16 | issue = 4 | pages = 306–16 | date = October 2005 | pmid = 16210110 | doi = 10.1053/j.spid.2005.06.010 }}</ref> By keeping E2F-DP inactivated, RB1 maintains the cell in the G1 phase, preventing progression through the cell cycle and acting as a growth suppressor.<ref name="Münger and Howley"/>  The Rb-E2F/DP complex also attracts a [[histone deacetylase]] (HDAC) protein to the [[chromatin]], reducing transcription of S phase promoting factors, further suppressing [[DNA synthesis]].
 
== Activation and inactivation ==
{{see also|cyclin-dependent kinase|DREAM complex}}
When it is time for a cell to enter S phase, complexes of [[cyclin-dependent kinase]]s (CDK) and [[cyclin]]s phosphorylate Rb to pRb, allowing E2F-DP to dissociate from pRb and become active.<ref name="Münger and Howley"/> When E2F is free it activates factors like [[cyclin]]s (e.g. [[cyclin E]] and [[cyclin A]]), which push the cell through the cell cycle by activating cyclin-dependent kinases, and a molecule called proliferating cell nuclear antigen, or [[PCNA]], which speeds DNA replication and [[DNA repair|repair]] by helping to attach [[DNA polymerase|polymerase]] to DNA.<ref name="Funk"/><ref name="Greenblatt"/><ref name="Das"/><ref name="Korenjak and Brehm"/><ref name="Münger and Howley"/><ref name="De Veylder"/><ref name="Das">{{cite journal | vauthors = Das SK, Hashimoto T, Shimizu K, Yoshida T, Sakai T, Sowa Y, Komoto A, Kanazawa K | title = Fucoxanthin induces cell cycle arrest at G0/G1 phase in human colon carcinoma cells through up-regulation of p21WAF1/Cip1 | journal = Biochim. Biophys. Acta | volume = 1726 | issue = 3 | pages = 328–35 | date = November 2005 | pmid = 16236452 | doi = 10.1016/j.bbagen.2005.09.007 }}</ref><ref name="Bartkova">{{cite journal | vauthors = Bartkova J, Grøn B, Dabelsteen E, Bartek J | title = Cell-cycle regulatory proteins in human wound healing | journal = Arch. Oral Biol. | volume = 48 | issue = 2 | pages = 125–32 | date = February 2003 | pmid = 12642231 | doi = 10.1016/S0003-9969(02)00202-9 }}</ref> The initial phosphorylation is performed by [[Cyclin D]]/[[CDK4]]/[[CDK6]], followed by additional phosphorylation by Cyclin E/CDK2. pRb remains phosphorylated throughout S, G2 and M phases.<ref name="Münger and Howley"/>
 
During the M-to-G1 transition, pRb is then progressively dephosphorylated by [[PP1]], returning to its growth-suppressive hypophosphorylated state Rb.<ref name="Münger and Howley"/><ref name="Vietri2006">{{cite journal | vauthors = Vietri M, Bianchi M, Ludlow JW, Mittnacht S, Villa-Moruzzi E | title = Direct interaction between the catalytic subunit of Protein Phosphatase 1 and pRb | journal = Cancer Cell Int. | volume = 6 | issue =  | pages = 3 | year = 2006 | pmid = 16466572 | pmc = 1382259 | doi = 10.1186/1475-2867-6-3 }}</ref>
 
Rb family proteins are components of the [[DREAM complex]] (also named LINC complex), which is composed of LIN9, LIN54, LIN37, MYBL2, RBL1, RBL2, RBBP4, TFDP1, TFDP2, E2F4 and E2F5. There is a testis-specific version of the complex, where LIN54, MYBL2 and RBBP4 are replaced by MTL5, MYBL1 and RBBP7, respectively. In Drosophila both DREAM versions also exist, the components being mip130 (lin9 homolog, replaced by aly in testes), mip120 (lin54 homolog, replaced by tomb in testes), and Myb, Caf1p55, DP, Mip40, E2F2, Rbf and Rbf2. The DREAM complex exists in quiescent cells in association with MuvB (consisting of HDAC1 or HDAC2, LIN52 and L3mbtl1, L3mbtl3 or L3mbtl4) where it represses cell cycle-dependent genes. DREAM dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2.
 
==Regeneration==
 
===Cochlea===
 
The retinoblastoma protein is involved in the growth and development of mammalian [[hair cell]]s of the [[cochlea]], and appears to be related to the cells' inability to regenerate. Embryonic hair cells require Rb, among other important proteins, to exit the cell-cycle and stop dividing, which allows maturation of the auditory system. Once wild-type mammals have reached adulthood, their cochlear hair cells become incapable of proliferation. In studies where the gene for Rb is deleted in mice cochlea, hair cells continue to proliferate in early adulthood. Though this may seem to be a positive development, Rb-knockdown mice tend to develop severe hearing loss due to degeneration of the [[organ of Corti]]. For this reason, Rb seems to be instrumental for completing the development of mammalian [[hair cell]]s and keeping them alive.<ref name="pmid16648263">{{cite journal | vauthors = Sage C, Huang M, Vollrath MA, Brown MC, Hinds PW, Corey DP, Vetter DE, Chen ZY | title = Essential role of retinoblastoma protein in mammalian hair cell development and hearing | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 103 | issue = 19 | pages = 7345–50 | year = 2006 | pmid = 16648263 | pmc = 1450112 | doi = 10.1073/pnas.0510631103 }}</ref><ref name="pmid18178626">{{cite journal | vauthors = Weber T, Corbett MK, Chow LM, Valentine MB, Baker SJ, Zuo J | title = Rapid cell-cycle reentry and cell death after acute inactivation of the retinoblastoma gene product in postnatal cochlear hair cells | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 2 | pages = 781–5 | year = 2008 | pmid = 18178626 | pmc = 2206613 | doi = 10.1073/pnas.0708061105 }}</ref> However, it is clear that without Rb, hair cells have the ability to proliferate, which is why Rb is known as a [[tumor]] suppressor. Temporarily and precisely turning off Rb in adult mammals with damaged hair cells may lead to propagation and therefore successful [[regeneration (biology)|regeneration]].  Suppressing function of the retinoblastoma protein in the adult rat cochlea has been found to cause proliferation of supporting cells and [[hair cell]]s. Rb can be downregulated by activating the [[sonic hedgehog]] pathway, which phosphorylates the proteins and reduces gene transcription.<ref name="pmid23211596">{{cite journal | vauthors = Lu N, Chen Y, Wang Z, Chen G, Lin Q, Chen ZY, Li H | title = Sonic hedgehog initiates cochlear hair cell regeneration through downregulation of retinoblastoma protein | journal = Biochem. Biophys. Res. Commun. | volume = 430 | issue = 2 | pages = 700–5 | year = 2013 | pmid = 23211596 | pmc = 3579567 | doi = 10.1016/j.bbrc.2012.11.088 }}</ref>
 
=== Neurons ===
 
Disrupting Rb expression in vitro, either by gene deletion or knockdown of Rb short interfering [[RNA]], causes dendrites to branch out farther. In addition, [[Schwann cell]]s, which provide essential support for the survival of neurons, travel with the [[neurite]]s, extending farther than normal. The inhibition of Rb supports the continued growth of nerve cells.<ref name="pmid24752312">{{cite journal | vauthors = Christie KJ, Krishnan A, Martinez JA, Purdy K, Singh B, Eaton S, Zochodne D | title = Enhancing adult nerve regeneration through the knockdown of retinoblastoma protein | journal = Nat Commun | volume = 5 | issue =  | pages = 3670 | year = 2014 | pmid = 24752312 | doi = 10.1038/ncomms4670 }}</ref>
 
== Interactions ==
 
Retinoblastoma protein has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[Abl gene]]<ref name="pmid9071815">{{cite journal | vauthors = Miyamura T, Nishimura J, Yufu Y, Nawata H | title = Interaction of BCR-ABL with the retinoblastoma protein in Philadelphia chromosome-positive cell lines | journal = Int. J. Hematol. | volume = 65 | issue = 2 | pages = 115–21 | date = February 1997 | pmid = 9071815 | doi = 10.1016/S0925-5710(96)00539-7 }}</ref><ref name="pmid8242749">{{cite journal | vauthors = Welch PJ, Wang JY | title = A C-terminal protein-binding domain in the retinoblastoma protein regulates nuclear c-Abl tyrosine kinase in the cell cycle | journal = Cell | volume = 75 | issue = 4 | pages = 779–90 | date = November 1993 | pmid = 8242749 | doi = 10.1016/0092-8674(93)90497-E }}</ref>
* [[Androgen receptor]]<ref name="pmid9813067">{{cite journal | vauthors = Lu J, Danielsen M | title = Differential regulation of androgen and glucocorticoid receptors by retinoblastoma protein | journal = J. Biol. Chem. | volume = 273 | issue = 47 | pages = 31528–33 | date = November 1998 | pmid = 9813067 | doi = 10.1074/jbc.273.47.31528 }}</ref><ref name="pmid9675141">{{cite journal | vauthors = Yeh S, Miyamoto H, Nishimura K, Kang H, Ludlow J, Hsiao P, Wang C, Su C, Chang C | title = Retinoblastoma, a tumor suppressor, is a coactivator for the androgen receptor in human prostate cancer DU145 cells | journal = Biochem. Biophys. Res. Commun. | volume = 248 | issue = 2 | pages = 361–7 | date = July 1998 | pmid = 9675141 | doi = 10.1006/bbrc.1998.8974 }}</ref>
* [[Apoptosis-antagonizing transcription factor]]<ref name="pmid12450794">{{cite journal | vauthors = Bruno T, De Angelis R, De Nicola F, Barbato C, Di Padova M, Corbi N, Libri V, Benassi B, Mattei E, Chersi A, Soddu S, Floridi A, Passananti C, Fanciulli M | title = Che-1 affects cell growth by interfering with the recruitment of HDAC1 by Rb | journal = Cancer Cell | volume = 2 | issue = 5 | pages = 387–99 | date = November 2002 | pmid = 12450794 | doi = 10.1016/S1535-6108(02)00182-4 }}</ref><ref name="pmid10783144">{{cite journal | vauthors = Fanciulli M, Bruno T, Di Padova M, De Angelis R, Iezzi S, Iacobini C, Floridi A, Passananti C | title = Identification of a novel partner of RNA polymerase II subunit 11, Che-1, which interacts with and affects the growth suppression function of Rb | journal = FASEB J. | volume = 14 | issue = 7 | pages = 904–12 | date = May 2000 | pmid = 10783144 | doi =  }}</ref>
* [[ARID4A]]<ref name="pmid10490602">{{cite journal | vauthors = Lai A, Lee JM, Yang WM, DeCaprio JA, Kaelin WG, Seto E, Branton PE | title = RBP1 Recruits Both Histone Deacetylase-Dependent and -Independent Repression Activities to Retinoblastoma Family Proteins | journal = Mol. Cell. Biol. | volume = 19 | issue = 10 | pages = 6632–41 | date = October 1999 | pmid = 10490602 | pmc = 84642 | doi =  10.1128/mcb.19.10.6632}}</ref>
* [[Aryl hydrocarbon receptor]]<ref name="pmid9712901">{{cite journal | vauthors = Ge NL, Elferink CJ | title = A direct interaction between the aryl hydrocarbon receptor and retinoblastoma protein. Linking dioxin signaling to the cell cycle | journal = J. Biol. Chem. | volume = 273 | issue = 35 | pages = 22708–13 | date = August 1998 | pmid = 9712901 | doi = 10.1074/jbc.273.35.22708 }}</ref>
* [[BRCA1]]<ref name="pmid10518542">{{cite journal | vauthors = Aprelikova ON, Fang BS, Meissner EG, Cotter S, Campbell M, Kuthiala A, Bessho M, Jensen RA, Liu ET | title = BRCA1-associated growth arrest is RB-dependent | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 21 | pages = 11866–71 | date = October 1999 | pmid = 10518542 | pmc = 18378 | doi = 10.1073/pnas.96.21.11866 }}</ref><ref name="pmid11521194">{{cite journal | vauthors = Fan S, Yuan R, Ma YX, Xiong J, Meng Q, Erdos M, Zhao JN, Goldberg ID, Pestell RG, Rosen EM | title = Disruption of BRCA1 LXCXE motif alters BRCA1 functional activity and regulation of RB family but not RB protein binding | journal = Oncogene | volume = 20 | issue = 35 | pages = 4827–41 | date = August 2001 | pmid = 11521194 | doi = 10.1038/sj.onc.1204666 }}</ref><ref name=pmid10220405/>
* [[BRF1 (gene)|BRF1]]<ref name="pmid11997511">{{cite journal | vauthors = Johnston IM, Allison SJ, Morton JP, Schramm L, Scott PH, White RJ | title = CK2 Forms a Stable Complex with TFIIIB and Activates RNA Polymerase III Transcription in Human Cells | journal = Mol. Cell. Biol. | volume = 22 | issue = 11 | pages = 3757–68 | date = June 2002 | pmid = 11997511 | pmc = 133823 | doi = 10.1128/MCB.22.11.3757-3768.2002 }}</ref><ref name="pmid10330166">{{cite journal | vauthors = Sutcliffe JE, Cairns CA, McLees A, Allison SJ, Tosh K, White RJ | title = RNA Polymerase III Transcription Factor IIIB Is a Target for Repression by Pocket Proteins p107 and p130 | journal = Mol. Cell. Biol. | volume = 19 | issue = 6 | pages = 4255–61 | date = June 1999 | pmid = 10330166 | pmc = 104385 | doi =  10.1128/mcb.19.6.4255}}</ref>
* [[C-jun]]<ref name="pmid10026157">{{cite journal | vauthors = Nishitani J, Nishinaka T, Cheng CH, Rong W, Yokoyama KK, Chiu R | title = Recruitment of the retinoblastoma protein to c-Jun enhances transcription activity mediated through the AP-1 binding site | journal = J. Biol. Chem. | volume = 274 | issue = 9 | pages = 5454–61 | date = February 1999 | pmid = 10026157 | doi = 10.1074/jbc.274.9.5454 }}</ref>
* [[C-Raf]]<ref name="pmid9819434">{{cite journal | vauthors = Wang S, Ghosh RN, Chellappan SP | title = Raf-1 Physically Interacts with Rb and Regulates Its Function: a Link between Mitogenic Signaling and Cell Cycle Regulation | journal = Mol. Cell. Biol. | volume = 18 | issue = 12 | pages = 7487–98 | date = December 1998 | pmid = 9819434 | pmc = 109329 | doi =  10.1128/mcb.18.12.7487}}</ref><ref name="pmid10523633">{{cite journal | vauthors = Wang S, Nath N, Fusaro G, Chellappan S | title = Rb and Prohibitin Target Distinct Regions of E2F1 for Repression and Respond to Different Upstream Signals | journal = Mol. Cell. Biol. | volume = 19 | issue = 11 | pages = 7447–60 | date = November 1999 | pmid = 10523633 | pmc = 84738 | doi =  10.1128/mcb.19.11.7447}}</ref>
* [[CDK9]]<ref name=pmid12037672/>
* [[CUTL1]]<ref name="pmid12891711">{{cite journal | vauthors = Gupta S, Luong MX, Bleuming SA, Miele A, Luong M, Young D, Knudsen ES, Van Wijnen AJ, Stein JL, Stein GS | title = Tumor suppressor pRB functions as a co-repressor of the CCAAT displacement protein (CDP/cut) to regulate cell cycle controlled histone H4 transcription | journal = J. Cell. Physiol. | volume = 196 | issue = 3 | pages = 541–56 | date = September 2003 | pmid = 12891711 | doi = 10.1002/jcp.10335 }}</ref>
* [[Cyclin A1]]<ref name="pmid10022926">{{cite journal | vauthors = Yang R, Müller C, Huynh V, Fung YK, Yee AS, Koeffler HP | title = Functions of Cyclin A1 in the Cell Cycle and Its Interactions with Transcription Factor E2F-1 and the Rb Family of Proteins | journal = Mol. Cell. Biol. | volume = 19 | issue = 3 | pages = 2400–7 | date = March 1999 | pmid = 10022926 | pmc = 84032 | doi =  10.1128/mcb.19.3.2400}}</ref>
* [[Cyclin D1]]<ref name="pmid11126356">{{cite journal | vauthors = Siegert JL, Rushton JJ, Sellers WR, Kaelin WG, Robbins PD | title = Cyclin D1 suppresses retinoblastoma protein-mediated inhibition of TAFII250 kinase activity | journal = Oncogene | volume = 19 | issue = 50 | pages = 5703–11 | date = November 2000 | pmid = 11126356 | doi = 10.1038/sj.onc.1203966 }}</ref><ref name="pmid8490963">{{cite journal | vauthors = Dowdy SF, Hinds PW, Louie K, Reed SI, Arnold A, Weinberg RA | title = Physical interaction of the retinoblastoma protein with human D cyclins | journal = Cell | volume = 73 | issue = 3 | pages = 499–511 | date = May 1993 | pmid = 8490963 | doi = 10.1016/0092-8674(93)90137-F }}</ref>
* [[Cyclin T2]]<ref name="pmid12037672">{{cite journal | vauthors = Simone C, Bagella L, Bellan C, Giordano A | title = Physical interaction between pRb and cdk9/cyclinT2 complex | journal = Oncogene | volume = 21 | issue = 26 | pages = 4158–65 | date = June 2002 | pmid = 12037672 | doi = 10.1038/sj.onc.1205511 }}</ref>
* [[DNMT1]]<ref name="pmid10888886">{{cite journal | vauthors = Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP | title = DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters | journal = Nat. Genet. | volume = 25 | issue = 3 | pages = 338–42 | date = July 2000 | pmid = 10888886 | doi = 10.1038/77124 }}</ref>
* [[E2F1]]<ref name="pmid11470869">{{cite journal | vauthors = Nicolas E, Ait-Si-Ali S, Trouche D | title = The histone deacetylase HDAC3 targets RbAp48 to the retinoblastoma protein | journal = Nucleic Acids Res. | volume = 29 | issue = 15 | pages = 3131–6 | date = August 2001 | pmid = 11470869 | pmc = 55834 | doi = 10.1093/nar/29.15.3131 }}</ref><ref name="pmid12397079">{{cite journal | vauthors = Pardo PS, Leung JK, Lucchesi JC, Pereira-Smith OM | title = MRG15, a novel chromodomain protein, is present in two distinct multiprotein complexes involved in transcriptional activation | journal = J. Biol. Chem. | volume = 277 | issue = 52 | pages = 50860–6 | date = December 2002 | pmid = 12397079 | doi = 10.1074/jbc.M203839200 }}</ref><ref name="pmid8896460">{{cite journal | vauthors = Choubey D, Li SJ, Datta B, Gutterman JU, Lengyel P | title = Inhibition of E2F-mediated transcription by p202 | journal = EMBO J. | volume = 15 | issue = 20 | pages = 5668–78 | date = October 1996 | pmid = 8896460 | pmc = 452311 | doi =  }}</ref><ref name="pmid10869426">{{cite journal | vauthors = Fajas L, Paul C, Zugasti O, Le Cam L, Polanowska J, Fabbrizio E, Medema R, Vignais ML, Sardet C | title = pRB binds to and modulates the transrepressing activity of the E1A-regulated transcription factor p120E4F | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 14 | pages = 7738–43 | date = July 2000 | pmid = 10869426 | pmc = 16614 | doi = 10.1073/pnas.130198397 }}</ref><ref name="pmid8230483">{{cite journal | vauthors = Dyson N, Dembski M, Fattaey A, Ngwu C, Ewen M, Helin K | title = Analysis of p107-associated proteins: p107 associates with a form of E2F that differs from pRB-associated E2F-1 | journal = J. Virol. | volume = 67 | issue = 12 | pages = 7641–7 | date = December 1993 | pmid = 8230483 | pmc = 238233 | doi =  }}</ref><ref name="pmid7739537">{{cite journal | vauthors = Wu CL, Zukerberg LR, Ngwu C, Harlow E, Lees JA | title = In vivo association of E2F and DP family proteins | journal = Mol. Cell. Biol. | volume = 15 | issue = 5 | pages = 2536–46 | date = May 1995 | pmid = 7739537 | pmc = 230484 | doi =  10.1128/mcb.15.5.2536}}</ref><ref name="pmid9422723">{{cite journal | vauthors = Taniura H, Taniguchi N, Hara M, Yoshikawa K | title = Necdin, a postmitotic neuron-specific growth suppressor, interacts with viral transforming proteins and cellular transcription factor E2F1 | journal = J. Biol. Chem. | volume = 273 | issue = 2 | pages = 720–8 | date = January 1998 | pmid = 9422723 | doi = 10.1074/jbc.273.2.720 }}</ref>
* [[E2F2]],<ref name="pmid12502741">{{cite journal | vauthors = Lee C, Chang JH, Lee HS, Cho Y | title = Structural basis for the recognition of the E2F transactivation domain by the retinoblastoma tumor suppressor | journal = Genes Dev. | volume = 16 | issue = 24 | pages = 3199–212 | date = December 2002 | pmid = 12502741 | pmc = 187509 | doi = 10.1101/gad.1046102 }}</ref>
* [[E4F1]]<ref name=pmid10869426/>
* [[EID1]]<ref name="pmid11073989">{{cite journal | vauthors = Miyake S, Sellers WR, Safran M, Li X, Zhao W, Grossman SR, Gan J, DeCaprio JA, Adams PD, Kaelin WG | title = Cells Degrade a Novel Inhibitor of Differentiation with E1A-Like Properties upon Exiting the Cell Cycle | journal = Mol. Cell. Biol. | volume = 20 | issue = 23 | pages = 8889–902 | date = December 2000 | pmid = 11073989 | pmc = 86544 | doi = 10.1128/MCB.20.23.8889-8902.2000 }}</ref><ref name="pmid11073990">{{cite journal | vauthors = MacLellan WR, Xiao G, Abdellatif M, Schneider MD | title = A Novel Rb- and p300-Binding Protein Inhibits Transactivation by MyoD | journal = Mol. Cell. Biol. | volume = 20 | issue = 23 | pages = 8903–15 | date = December 2000 | pmid = 11073990 | pmc = 86545 | doi = 10.1128/MCB.20.23.8903-8915.2000 }}</ref>
* [[ENC1]]<ref name="pmid9566959">{{cite journal | vauthors = Kim TA, Lim J, Ota S, Raja S, Rogers R, Rivnay B, Avraham H, Avraham S | title = NRP/B, a Novel Nuclear Matrix Protein, Associates With p110RB and Is Involved in Neuronal Differentiation | journal = J. Cell Biol. | volume = 141 | issue = 3 | pages = 553–66 | date = May 1998 | pmid = 9566959 | pmc = 2132755 | doi = 10.1083/jcb.141.3.553 }}</ref>
* [[FRK (gene)|FRK]]<ref name="pmid7664264">{{cite journal | vauthors = Craven RJ, Cance WG, Liu ET | title = The nuclear tyrosine kinase Rak associates with the retinoblastoma protein pRb | journal = Cancer Res. | volume = 55 | issue = 18 | pages = 3969–72 | date = September 1995 | pmid = 7664264 | doi =  }}</ref>
* [[HBP1]]<ref name="pmid9178770">{{cite journal | vauthors = Lavender P, Vandel L, Bannister AJ, Kouzarides T | title = The HMG-box transcription factor HBP1 is targeted by the pocket proteins and E1A | journal = Oncogene | volume = 14 | issue = 22 | pages = 2721–8 | date = June 1997 | pmid = 9178770 | doi = 10.1038/sj.onc.1201243 }}</ref>
* [[HDAC1]]<ref name=pmid10490602/><ref name=pmid10779361/><ref name="pmid10615135">{{cite journal | vauthors = Fuks F, Burgers WA, Brehm A, Hughes-Davies L, Kouzarides T | title = DNA methyltransferase Dnmt1 associates with histone deacetylase activity | journal = Nat. Genet. | volume = 24 | issue = 1 | pages = 88–91 | date = January 2000 | pmid = 10615135 | doi = 10.1038/71750 }}</ref><ref name="pmid11684023">{{cite journal | vauthors = Puri PL, Iezzi S, Stiegler P, Chen TT, Schiltz RL, Muscat GE, Giordano A, Kedes L, Wang JY, Sartorelli V | title = Class I histone deacetylases sequentially interact with MyoD and pRb during skeletal myogenesis | journal = Mol. Cell | volume = 8 | issue = 4 | pages = 885–97 | date = October 2001 | pmid = 11684023 | doi = 10.1016/S1097-2765(01)00373-2 }}</ref><ref name="pmid12466959">{{cite journal | vauthors = Wang S, Fusaro G, Padmanabhan J, Chellappan SP | title = Prohibitin co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for transcriptional repression | journal = Oncogene | volume = 21 | issue = 55 | pages = 8388–96 | date = December 2002 | pmid = 12466959 | doi = 10.1038/sj.onc.1205944 }}</ref><ref name="pmid9491888">{{cite journal | vauthors = Luo RX, Postigo AA, Dean DC | title = Rb interacts with histone deacetylase to repress transcription | journal = Cell | volume = 92 | issue = 4 | pages = 463–73 | date = February 1998 | pmid = 9491888 | doi = 10.1016/S0092-8674(00)80940-X }}</ref><ref name="pmid9724731">{{cite journal | vauthors = Ferreira R, Magnaghi-Jaulin L, Robin P, Harel-Bellan A, Trouche D | title = The three members of the pocket proteins family share the ability to repress E2F activity through recruitment of a histone deacetylase | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 18 | pages = 10493–8 | date = September 1998 | pmid = 9724731 | pmc = 27922 | doi = 10.1073/pnas.95.18.10493 }}</ref>
* [[HDAC3]]<ref name=pmid10490602/><ref name="pmid12479814">{{cite journal | vauthors = Fajas L, Egler V, Reiter R, Hansen J, Kristiansen K, Debril MB, Miard S, Auwerx J | title = The retinoblastoma-histone deacetylase 3 complex inhibits PPARgamma and adipocyte differentiation | journal = Dev. Cell | volume = 3 | issue = 6 | pages = 903–10 | date = December 2002 | pmid = 12479814 | doi = 10.1016/S1534-5807(02)00360-X }}</ref>
* [[Histone deacetylase 2]]<ref name=pmid10490602/>
* [[Insulin]]<ref name="pmid7818556">{{cite journal | vauthors = Radulescu RT, Bellitti MR, Ruvo M, Cassani G, Fassina G | title = Binding of the LXCXE Insulin Motif to a Hexapeptide Derived from Retinoblastoma Protein | journal = Biochemical and Biophysical Research Communications | volume = 206 | issue = 1 | pages = 97–102 | date = January 1995 | pmid = 7818556 | doi = 10.1006/bbrc.1995.1014 }}</ref>
* [[JARID1A]]<ref name="pmid11358960">{{cite journal | vauthors = Chan SW, Hong W | title = Retinoblastoma-binding protein 2 (Rbp2) potentiates nuclear hormone receptor-mediated transcription | journal = J. Biol. Chem. | volume = 276 | issue = 30 | pages = 28402–12 | date = July 2001 | pmid = 11358960 | doi = 10.1074/jbc.M100313200 }}</ref><ref name="pmid7935440">{{cite journal | vauthors = Kim YW, Otterson GA, Kratzke RA, Coxon AB, Kaye FJ | title = Differential specificity for binding of retinoblastoma binding protein 2 to RB, p107, and TATA-binding protein | journal = Mol. Cell. Biol. | volume = 14 | issue = 11 | pages = 7256–64 | date = November 1994 | pmid = 7935440 | pmc = 359260 | doi =  10.1128/mcb.14.11.7256}}</ref>
* [[LIN9]]<ref name="pmid15538385">{{cite journal | vauthors = Gagrica S, Hauser S, Kolfschoten I, Osterloh L, Agami R, Gaubatz S | title = Inhibition of oncogenic transformation by mammalian Lin-9, a pRB-associated protein | journal = EMBO J. | volume = 23 | issue = 23 | pages = 4627–38 | date = November 2004 | pmid = 15538385 | pmc = 533054 | doi = 10.1038/sj.emboj.7600470 }}</ref>
* [[MCM7]]<ref name="pmid9566894">{{cite journal | vauthors = Sterner JM, Dew-Knight S, Musahl C, Kornbluth S, Horowitz JM | title = Negative Regulation of DNA Replication by the Retinoblastoma Protein Is Mediated by Its Association with MCM7 | journal = Mol. Cell. Biol. | volume = 18 | issue = 5 | pages = 2748–57 | date = May 1998 | pmid = 9566894 | pmc = 110654 | doi =  10.1128/mcb.18.5.2748}}</ref>
* [[MORF4L1]]<ref name=pmid12397079/><ref name=pmid11500496/>
* [[MRFAP1]],<ref name=pmid12397079/><ref name="pmid11500496">{{cite journal | vauthors = Leung JK, Berube N, Venable S, Ahmed S, Timchenko N, Pereira-Smith OM | title = MRG15 activates the B-myb promoter through formation of a nuclear complex with the retinoblastoma protein and the novel protein PAM14 | journal = J. Biol. Chem. | volume = 276 | issue = 42 | pages = 39171–8 | date = October 2001 | pmid = 11500496 | doi = 10.1074/jbc.M103435200 }}</ref>
* [[MyoD]]<ref name="pmid11285237">{{cite journal | vauthors = Mal A, Sturniolo M, Schiltz RL, Ghosh MK, Harter ML | title = A role for histone deacetylase HDAC1 in modulating the transcriptional activity of MyoD: inhibition of the myogenic program | journal = EMBO J. | volume = 20 | issue = 7 | pages = 1739–53 | date = April 2001 | pmid = 11285237 | pmc = 145490 | doi = 10.1093/emboj/20.7.1739 }}</ref><ref name="pmid8381715">{{cite journal | vauthors = Gu W, Schneider JW, Condorelli G, Kaushal S, Mahdavi V, Nadal-Ginard B | title = Interaction of myogenic factors and the retinoblastoma protein mediates muscle cell commitment and differentiation | journal = Cell | volume = 72 | issue = 3 | pages = 309–24 | date = February 1993 | pmid = 8381715 | doi = 10.1016/0092-8674(93)90110-C }}</ref>
* [[NCOA6]]<ref name="pmid14645241">{{cite journal | vauthors = Goo YH, Na SY, Zhang H, Xu J, Hong S, Cheong J, Lee SK, Lee JW | title = Interactions between activating signal cointegrator-2 and the tumor suppressor retinoblastoma in androgen receptor transactivation | journal = J. Biol. Chem. | volume = 279 | issue = 8 | pages = 7131–5 | date = February 2004 | pmid = 14645241 | doi = 10.1074/jbc.M312563200 }}</ref>
* [[PA2G4]]<ref name="pmid11268000">{{cite journal | vauthors = Xia X, Cheng A, Lessor T, Zhang Y, Hamburger AW | title = Ebp1, an ErbB-3 binding protein, interacts with Rb and affects Rb transcriptional regulation | journal = J. Cell. Physiol. | volume = 187 | issue = 2 | pages = 209–17 | date = May 2001 | pmid = 11268000 | doi = 10.1002/jcp.1075 }}</ref>
* [[Peroxisome proliferator-activated receptor gamma]]<ref name=pmid12479814/>
* [[PIK3R3]]<ref name="pmid12588990">{{cite journal | vauthors = Xia X, Cheng A, Akinmade D, Hamburger AW | title = The N-Terminal 24 Amino Acids of the p55 Gamma Regulatory Subunit of Phosphoinositide 3-Kinase Binds Rb and Induces Cell Cycle Arrest | journal = Mol. Cell. Biol. | volume = 23 | issue = 5 | pages = 1717–25 | date = March 2003 | pmid = 12588990 | pmc = 151709 | doi = 10.1128/MCB.23.5.1717-1725.2003 }}</ref>
* [[Plasminogen activator inhibitor-2]]<ref name="pmid12944478">{{cite journal | vauthors = Darnell GA, Antalis TM, Johnstone RW, Stringer BW, Ogbourne SM, Harrich D, Suhrbier A | title = Inhibition of Retinoblastoma Protein Degradation by Interaction with the Serpin Plasminogen Activator Inhibitor 2 via a Novel Consensus Motif | journal = Mol. Cell. Biol. | volume = 23 | issue = 18 | pages = 6520–32 | date = September 2003 | pmid = 12944478 | pmc = 193706 | doi = 10.1128/MCB.23.18.6520-6532.2003 }}</ref>
* [[Polymerase (DNA directed), alpha 1]]<ref name="pmid9395244">{{cite journal | vauthors = Takemura M, Kitagawa T, Izuta S, Wasa J, Takai A, Akiyama T, Yoshida S | title = Phosphorylated retinoblastoma protein stimulates DNA polymerase alpha | journal = Oncogene | volume = 15 | issue = 20 | pages = 2483–92 | date = November 1997 | pmid = 9395244 | doi = 10.1038/sj.onc.1201431 }}</ref>
* [[PRDM2]]<ref name="pmid7538672">{{cite journal | vauthors = Buyse IM, Shao G, Huang S | title = The retinoblastoma protein binds to RIZ, a zinc-finger protein that shares an epitope with the adenovirus E1A protein | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 92 | issue = 10 | pages = 4467–71 | date = May 1995 | pmid = 7538672 | pmc = 41965 | doi = 10.1073/pnas.92.10.4467 }}</ref>
* [[PRKRA]]<ref name="pmid9010216">{{cite journal | vauthors = Simons A, Melamed-Bessudo C, Wolkowicz R, Sperling J, Sperling R, Eisenbach L, Rotter V | title = PACT: cloning and characterization of a cellular p53 binding protein that interacts with Rb | journal = Oncogene | volume = 14 | issue = 2 | pages = 145–55 | date = January 1997 | pmid = 9010216 | doi = 10.1038/sj.onc.1200825 }}</ref>
* [[Prohibitin]]<ref name=pmid10523633/><ref name="pmid10376528">{{cite journal | vauthors = Wang S, Nath N, Adlam M, Chellappan S | title = Prohibitin, a potential tumor suppressor, interacts with RB and regulates E2F function | journal = Oncogene | volume = 18 | issue = 23 | pages = 3501–10 | date = June 1999 | pmid = 10376528 | doi = 10.1038/sj.onc.1202684 }}</ref>
* [[Promyelocytic leukemia protein]]<ref name="pmid9448006">{{cite journal | vauthors = Alcalay M, Tomassoni L, Colombo E, Stoldt S, Grignani F, Fagioli M, Szekely L, Helin K, Pelicci PG | title = The Promyelocytic Leukemia Gene Product (PML) Forms Stable Complexes with the Retinoblastoma Protein | journal = Mol. Cell. Biol. | volume = 18 | issue = 2 | pages = 1084–93 | date = February 1998 | pmid = 9448006 | pmc = 108821 | doi =  10.1128/mcb.18.2.1084}}</ref>
* [[RBBP4]]<ref name=pmid11470869/><ref name="pmid7503932">{{cite journal | vauthors = Qian YW, Lee EY | title = Dual retinoblastoma-binding proteins with properties related to a negative regulator of ras in yeast | journal = J. Biol. Chem. | volume = 270 | issue = 43 | pages = 25507–13 | date = October 1995 | pmid = 7503932 | doi = 10.1074/jbc.270.43.25507 }}</ref>
* [[RBBP7]]<ref name="pmid10220405">{{cite journal | vauthors = Yarden RI, Brody LC | title = BRCA1 interacts with components of the histone deacetylase complex | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 9 | pages = 4983–8 | date = April 1999 | pmid = 10220405 | pmc = 21803 | doi = 10.1073/pnas.96.9.4983 }}</ref><ref name="pmid7503932"/>
* [[RBBP8]]<ref name="pmid10779361">{{cite journal | vauthors = Dick FA, Sailhamer E, Dyson NJ | title = Mutagenesis of the pRB Pocket Reveals that Cell Cycle Arrest Functions Are Separable from Binding to Viral Oncoproteins | journal = Mol. Cell. Biol. | volume = 20 | issue = 10 | pages = 3715–27 | date = May 2000 | pmid = 10779361 | pmc = 85672 | doi = 10.1128/MCB.20.10.3715-3727.2000 }}</ref><ref name="pmid9721205">{{cite journal | vauthors = Fusco C, Reymond A, Zervos AS | title = Molecular cloning and characterization of a novel retinoblastoma-binding protein | journal = Genomics | volume = 51 | issue = 3 | pages = 351–8 | date = August 1998 | pmid = 9721205 | doi = 10.1006/geno.1998.5368 }}</ref>
* [[RBBP9]]<ref name="pmid9697699">{{cite journal | vauthors = Woitach JT, Zhang M, Niu CH, Thorgeirsson SS | title = A retinoblastoma-binding protein that affects cell-cycle control and confers transforming ability | journal = Nat. Genet. | volume = 19 | issue = 4 | pages = 371–4 | date = August 1998 | pmid = 9697699 | doi = 10.1038/1258 }}</ref>
* [[SNAPC1]]<ref name="pmid11094070">{{cite journal | vauthors = Hirsch HA, Gu L, Henry RW | title = The Retinoblastoma Tumor Suppressor Protein Targets Distinct General Transcription Factors To Regulate RNA Polymerase III Gene Expression | journal = Mol. Cell. Biol. | volume = 20 | issue = 24 | pages = 9182–91 | date = December 2000 | pmid = 11094070 | pmc = 102176 | doi = 10.1128/MCB.20.24.9182-9191.2000 }}</ref>
* [[SKP2]]<ref name="pmid15469821">{{cite journal | vauthors = Ji P, Jiang H, Rekhtman K, Bloom J, Ichetovkin M, Pagano M, Zhu L | title = An Rb-Skp2-p27 pathway mediates acute cell cycle inhibition by Rb and is retained in a partial-penetrance Rb mutant | journal = Mol. Cell | volume = 16 | issue = 1 | pages = 47–58 | date = October 2004 | pmid = 15469821 | doi = 10.1016/j.molcel.2004.09.029 }}</ref><ref name="pmid19966802">{{cite journal | vauthors = Wang H, Bauzon F, Ji P, Xu X, Sun D, Locker J, Sellers RS, Nakayama K, Nakayama KI, Cobrinik D, Zhu L | title = Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/- mice | journal = Nat. Genet. | volume = 42 | issue = 1 | pages = 83–8 | date = January 2010 | pmid = 19966802 | pmc = 2990528 | doi = 10.1038/ng.498 }}</ref>
* [[SNAPC3]]<ref name=pmid11094070/>
* [[SNW1]]<ref name="pmid12466551">{{cite journal | vauthors = Prathapam T, Kühne C, Banks L | title = Skip interacts with the retinoblastoma tumor suppressor and inhibits its transcriptional repression activity | journal = Nucleic Acids Res. | volume = 30 | issue = 23 | pages = 5261–8 | date = December 2002 | pmid = 12466551 | pmc = 137971 | doi = 10.1093/nar/gkf658 }}</ref>
* [[SUV39H1]]<ref name="pmid11484059">{{cite journal | vauthors = Nielsen SJ, Schneider R, Bauer UM, Bannister AJ, Morrison A, O'Carroll D, Firestein R, Cleary M, Jenuwein T, Herrera RE, Kouzarides T | title = Rb targets histone H3 methylation and HP1 to promoters | journal = Nature | volume = 412 | issue = 6846 | pages = 561–5 | date = August 2001 | pmid = 11484059 | doi = 10.1038/35087620 }}</ref><ref name="pmid11533237">{{cite journal | vauthors = Vandel L, Nicolas E, Vaute O, Ferreira R, Ait-Si-Ali S, Trouche D | title = Transcriptional Repression by the Retinoblastoma Protein through the Recruitment of a Histone Methyltransferase | journal = Mol. Cell. Biol. | volume = 21 | issue = 19 | pages = 6484–94 | date = October 2001 | pmid = 11533237 | pmc = 99795 | doi = 10.1128/MCB.21.19.6484-6494.2001 }}</ref>
* [[TAF1]]<ref name=pmid11126356/><ref name="pmid7724524">{{cite journal | vauthors = Shao Z, Ruppert S, Robbins PD | title = The retinoblastoma-susceptibility gene product binds directly to the human TATA-binding protein-associated factor TAFII250 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 92 | issue = 8 | pages = 3115–9 | date = April 1995 | pmid = 7724524 | pmc = 42115 | doi = 10.1073/pnas.92.8.3115 }}</ref><ref name="pmid9858607">{{cite journal | vauthors = Siegert JL, Robbins PD | title = Rb Inhibits the Intrinsic Kinase Activity of TATA-Binding Protein-Associated Factor TAFII250 | journal = Mol. Cell. Biol. | volume = 19 | issue = 1 | pages = 846–54 | date = January 1999 | pmid = 9858607 | pmc = 83941 | doi =  }}</ref><ref name="pmid9242374">{{cite journal | vauthors = Shao Z, Siegert JL, Ruppert S, Robbins PD | title = Rb interacts with TAF(II)250/TFIID through multiple domains | journal = Oncogene | volume = 15 | issue = 4 | pages = 385–92 | date = July 1997 | pmid = 9242374 | doi = 10.1038/sj.onc.1201204 }}</ref>
* [[THOC1]]<ref name="pmid7525595">{{cite journal | vauthors = Durfee T, Mancini MA, Jones D, Elledge SJ, Lee WH | title = The amino-terminal region of the retinoblastoma gene product binds a novel nuclear matrix protein that co-localizes to centers for RNA processing | journal = J. Cell Biol. | volume = 127 | issue = 3 | pages = 609–22 | date = November 1994 | pmid = 7525595 | pmc = 2120229 | doi = 10.1083/jcb.127.3.609 }}</ref>
* [[TRAP1]]<ref name="pmid8756626">{{cite journal | vauthors = Chen CF, Chen Y, Dai K, Chen PL, Riley DJ, Lee WH | title = A new member of the hsp90 family of molecular chaperones interacts with the retinoblastoma protein during mitosis and after heat shock | journal = Mol. Cell. Biol. | volume = 16 | issue = 9 | pages = 4691–9 | date = September 1996 | pmid = 8756626 | pmc = 231469 | doi =  }}</ref>
* [[TRIP11]]<ref name="pmid9256431">{{cite journal | vauthors = Chang KH, Chen Y, Chen TT, Chou WH, Chen PL, Ma YY, Yang-Feng TL, Leng X, Tsai MJ, O'Malley BW, Lee WH | title = A thyroid hormone receptor coactivator negatively regulated by the retinoblastoma protein | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 94 | issue = 17 | pages = 9040–5 | date = August 1997 | pmid = 9256431 | pmc = 23019 | doi = 10.1073/pnas.94.17.9040 }}</ref>
* [[UBTF]]<ref name="pmid11042686">{{cite journal | vauthors = Hannan KM, Hannan RD, Smith SD, Jefferson LS, Lun M, Rothblum LI | title = Rb and p130 regulate RNA polymerase I transcription: Rb disrupts the interaction between UBF and SL-1 | journal = Oncogene | volume = 19 | issue = 43 | pages = 4988–99 | date = October 2000 | pmid = 11042686 | doi = 10.1038/sj.onc.1203875 }}</ref>
* [[USP4]].<ref name="pmid11571651">{{cite journal | vauthors = Blanchette P, Gilchrist CA, Baker RT, Gray DA | title = Association of UNP, a ubiquitin-specific protease, with the pocket proteins pRb, p107 and p130 | journal = Oncogene | volume = 20 | issue = 39 | pages = 5533–7 | date = September 2001 | pmid = 11571651 | doi = 10.1038/sj.onc.1204823 }}</ref>
{{Div col end}}
 
== Detection ==
 
Several methods for detecting the RB1 gene mutations have been developed<ref name="pmid20090211">{{cite journal | vauthors = Parsam VL, Kannabiran C, Honavar S, Vemuganti GK, Ali MJ | title = A comprehensive, sensitive and economical approach for the detection of mutations in the RB1 gene in retinoblastoma | journal = J. Genet. | volume = 88 | issue = 4 | pages = 517–27 | date = December 2009 | pmid = 20090211 | doi = 10.1007/s12041-009-0069-z | url = http://www.ias.ac.in/jgenet/Vol88No4/517.pdf }}</ref> including a method that can detect large deletions that correlate with advanced stage retinoblastoma.<ref name="Ali_2010">{{cite journal | vauthors = Ali MJ, Parsam VL, Honavar SG, Kannabiran C, Vemuganti GK, Reddy VA | title = RB1 gene mutations in retinoblastoma and its clinical correlation | journal = Saudi Journal of Ophthalmology | volume = 24 | issue = 4 | pages = 119–123 | year = 2010 | pmid = 23960888 | doi = 10.1016/j.sjopt.2010.05.003 }}</ref>
 
[[Image:Signal transduction v1.png|300px|thumb|center|Overview of signal transduction pathways involved in [[apoptosis]].]]
 
== See also ==
* [[p53]] - involved in the DNA repair support function of pRb
* [[p53]] - involved in the DNA repair support function of pRb
* [[Transcription coregulator]]
* [[Transcription coregulator]]
* [[Retinoblastoma]]


==References==
== References ==
{{reflist|2}}
{{Reflist|colwidth=35em}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{Refbegin|colwidth=35em}}
{{PBB_Further_reading
* {{cite journal | vauthors = Momand J, Wu HH, Dasgupta G | title = MDM2—master regulator of the p53 tumor suppressor protein | journal = Gene | volume = 242 | issue = 1–2 | pages = 15–29 | year = 2000 | pmid = 10721693 | doi = 10.1016/S0378-1119(99)00487-4 }}
| citations =
* {{cite journal | vauthors = Zheng L, Lee WH | title = Retinoblastoma tumor suppressor and genome stability | journal = Adv. Cancer Res. | volume = 85 | issue =  | pages = 13–50 | year = 2003 | pmid = 12374284 | doi = 10.1016/S0065-230X(02)85002-3 | isbn = 978-0-12-006685-8 | series = Advances in Cancer Research }}
*{{cite journal | author=Momand J, Wu HH, Dasgupta G |title=MDM2--master regulator of the p53 tumor suppressor protein. |journal=Gene |volume=242 |issue= 1-2 |pages= 15-29 |year= 2000 |pmid= 10721693 |doi= }}
* {{cite journal | vauthors = Classon M, Harlow E | title = The retinoblastoma tumour suppressor in development and cancer | journal = Nature Reviews Cancer | volume = 2 | issue = 12 | pages = 910–7 | year = 2003 | pmid = 12459729 | doi = 10.1038/nrc950 }}
*{{cite journal | author=Zheng L, Lee WH |title=Retinoblastoma tumor suppressor and genome stability. |journal=Adv. Cancer Res. |volume=85 |issue=  |pages= 13-50 |year= 2003 |pmid= 12374284 |doi= }}
* {{cite journal | vauthors = Lai H, Ma F, Lai S | title = Identification of the novel role of pRB in eye cancer | journal = J. Cell. Biochem. | volume = 88 | issue = 1 | pages = 121–7 | year = 2003 | pmid = 12461781 | doi = 10.1002/jcb.10283 }}
*{{cite journal | author=Classon M, Harlow E |title=The retinoblastoma tumour suppressor in development and cancer. |journal=Nat. Rev. Cancer |volume=2 |issue= 12 |pages= 910-7 |year= 2003 |pmid= 12459729 |doi= 10.1038/nrc950 }}
* {{cite journal | vauthors = Simin K, Wu H, Lu L, Pinkel D, Albertson D, Cardiff RD, Van Dyke T | title = pRb Inactivation in Mammary Cells Reveals Common Mechanisms for Tumor Initiation and Progression in Divergent Epithelia | journal = PLoS Biol. | volume = 2 | issue = 2 | pages = E22 | year = 2006 | pmid = 14966529 | pmc = 340938 | doi = 10.1371/journal.pbio.0020022 }}
*{{cite journal | author=Lai H, Ma F, Lai S |title=Identification of the novel role of pRB in eye cancer. |journal=J. Cell. Biochem. |volume=88 |issue= 1 |pages= 121-7 |year= 2003 |pmid= 12461781 |doi= 10.1002/jcb.10283 }}
* {{cite journal | vauthors = Lohmann DR, Gallie BL | title = Retinoblastoma: revisiting the model prototype of inherited cancer | journal = American Journal of Medical Genetics | volume = 129 | issue = 1 | pages = 23–8 | year = 2004 | pmid = 15264269 | doi = 10.1002/ajmg.c.30024 }}
*{{cite journal | author=Simin K, Wu H, Lu L, ''et al.'' |title=pRb inactivation in mammary cells reveals common mechanisms for tumor initiation and progression in divergent epithelia. |journal=PLoS Biol. |volume=2 |issue= 2 |pages= E22 |year= 2006 |pmid= 14966529 |doi= 10.1371/journal.pbio.0020022 }}
* {{cite journal | vauthors = Clemo NK, Arhel NJ, Barnes JD, Baker J, Moorghen M, Packham GK, Paraskeva C, Williams AC | title = The role of the retinoblastoma protein (Rb) in the nuclear localization of BAG-1: implications for colorectal tumour cell survival | journal = Biochem. Soc. Trans. | volume = 33 | issue = Pt 4 | pages = 676–8 | year = 2005 | pmid = 16042572 | doi = 10.1042/BST0330676 }}
*{{cite journal | author=Lohmann DR, Gallie BL |title=Retinoblastoma: revisiting the model prototype of inherited cancer. |journal=American journal of medical genetics. Part C, Seminars in medical genetics |volume=129 |issue= 1 |pages= 23-8 |year= 2004 |pmid= 15264269 |doi= 10.1002/ajmg.c.30024 }}
* {{cite journal | vauthors = Rodríguez-Cruz M, del Prado M, Salcedo M | title = Genomic retinoblastoma perspectives: implications of tumor suppressor gene RB1 | journal = Rev. Invest. Clin. | volume = 57 | issue = 4 | pages = 572–81 | year = 2006 | pmid = 16315642 | doi =  }}
*{{cite journal | author=Clemo NK, Arhel NJ, Barnes JD, ''et al.'' |title=The role of the retinoblastoma protein (Rb) in the nuclear localization of BAG-1: implications for colorectal tumour cell survival. |journal=Biochem. Soc. Trans. |volume=33 |issue= Pt 4 |pages= 676-8 |year= 2005 |pmid= 16042572 |doi= 10.1042/BST0330676 }}
* {{cite journal | vauthors = Knudsen ES, Knudsen KE | title = Retinoblastoma tumor suppressor: where cancer meets the cell cycle | journal = Exp. Biol. Med. (Maywood) | volume = 231 | issue = 7 | pages = 1271–81 | year = 2006 | pmid = 16816134 | doi =  }}
*{{cite journal | author=Rodríguez-Cruz M, del Prado M, Salcedo M |title=[Genomic retinoblastoma perspectives: implications of tumor supressor gene RB1] |journal=Rev. Invest. Clin. |volume=57 |issue= 4 |pages= 572-81 |year= 2006 |pmid= 16315642 |doi=  }}
{{Refend}}
*{{cite journal | author=Knudsen ES, Knudsen KE |title=Retinoblastoma tumor suppressor: where cancer meets the cell cycle. |journal=Exp. Biol. Med. (Maywood) |volume=231 |issue= 7 |pages= 1271-81 |year= 2006 |pmid= 16816134 |doi=  }}
}}
{{refend}}


==External links==
== External links ==
* {{MeshName|RB1+protein,+human}}
* {{MeshName|RB1+protein,+human}}
* {{MeshName|Retinoblastoma+genes}}
* {{MeshName|Retinoblastoma+genes}}
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=retinoblastoma  GeneReviews/NIH/NCBI/UW entry on Retinoblastoma]
* [http://rb1-lsdb.d-lohmann.de/ Retinoblastoma Genetics]
* [http://rb1-lsdb.d-lohmann.de/ Retinoblastoma Genetics]
* [http://www.sdbonline.org/fly/newgene/retnbls1.htm ''Drosophila'' ''Retinoblastoma-family protein'' - The Interactive Fly]
* [http://www.sdbonline.org/fly/genebrief/rbf2.htm ''Drosophila'' ''Retinoblastoma-family protein 2'' - The Interactive Fly]
* [http://www.sdbonline.org/fly/newgene/retnbs2e.htm ''Evolutionary Homologs'' ''Retinoblastoma-family proteins'' - The Interactive Fly]
* There is a diagram of the pRb-E2F interactions [http://courses.biology.utah.edu/golic/2030/Cell%20cycle:cancer/cyclin:cdk%20control.jpg here].
* There is a diagram of the pRb-E2F interactions [http://courses.biology.utah.edu/golic/2030/Cell%20cycle:cancer/cyclin:cdk%20control.jpg here].


{{protein-stub}}
{{NLM content}}
{{NLM content}}
{{PDB Gallery|geneid=5925}}
{{Transcription coregulators}}
{{Transcription coregulators}}
{{Transcription factors}}
{{Transcription factors|g0}}
{{Tumor suppressor genes}}
{{Tumor suppressor genes}}
{{DEFAULTSORT:Retinoblastoma Protein}}
[[Category:DNA replication]]
[[Category:DNA replication]]
[[Category:Gene expression]]
[[Category:Gene expression]]
[[Category:Proteins]]
[[Category:Transcription coregulators]]
[[Category:Transcription coregulators]]
[[Category:Transcription factors]]
[[Category:Transcription factors]]
 
[[Category:Tumor suppressor genes]]
[[es:Proteína del retinoblastoma]]
[[fr:Protéine du rétinoblastome]]
[[it:Proteina del retinoblastoma]]
[[pl:RB1]]
 
{{WH}}
 
{{WS}}

Revision as of 20:47, 8 November 2017

"RB1" redirects here. For the automobile, see Red Bull RB1.
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The retinoblastoma protein (protein name abbreviated pRb; gene name abbreviated RB or RB1) is a tumor suppressor protein that is dysfunctional in several major cancers.[1] One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. When the cell is ready to divide, pRb is phosphorylated, becomes inactive and allows cell cycle progression. It is also a recruiter of several chromatin remodeling enzymes such as methylases and acetylases.[2]

Rb belongs to the pocket protein family, whose members have a pocket for the functional binding of other proteins.[3][4] Should an oncogenic protein, such as those produced by cells infected by high-risk types of human papillomaviruses, bind and inactivate pRb, this can lead to cancer. The RB gene may have been responsible for the evolution of multicellularity in several lineages of life including animals.[5]

Name and genetics

In humans, the protein is encoded by the RB1 gene located on chromosome 13—more specifically, 13q14.1-q14.2. If both alleles of this gene are mutated early in life, the protein is inactivated and results in development of retinoblastoma cancer, hence the name Rb. Retinal cells are not sloughed off or replaced, and are subjected to high levels of mutagenic UV radiation, and thus most pRB knock-outs occur in retinal tissue (but it's also been documented in certain skin cancers in patients from New Zealand where the amount of UV radiation is significantly higher).

Two forms of retinoblastoma were noticed: a bilateral, familial form and a unilateral, sporadic form. Sufferers of the former were 6 times more likely to develop other types of cancer later in life.[6] This highlighted the fact that mutated Rb could be inherited and lent support to the two-hit hypothesis. This states that only one working allele of a tumour suppressor gene is necessary for its function (the mutated gene is recessive), and so both need to be mutated before the cancer phenotype will appear. In the familial form, a mutated allele is inherited along with a normal allele. In this case, should a cell sustain only one mutation in the other RB gene, all Rb in that cell would be ineffective at inhibiting cell cycle progression, allowing cells to divide uncontrollably and eventually become cancerous. Furthermore, as one allele is already mutated in all other somatic cells, the future incidence of cancers in these individuals is observed with linear kinetics.[7] The working allele need not undergo a mutation per se, as loss of heterozygosity (LOH) is frequently observed in such tumours.

However, in the sporadic form, both alleles would need to sustain a mutation before the cell can become cancerous. This explains why sufferers of sporadic retinoblastoma are not at increased risk of cancers later in life, as both alleles are functional in all their other cells. Future cancer incidence in sporadic Rb cases is observed with polynomial kinetics, not exactly quadratic as expected because the first mutation must arise through normal mechanisms, and then can be duplicated by LOH to result in a tumour progenitor.

RB1 orthologs[8] have also been identified in most mammals for which complete genome data are available.

RB/E2F-family proteins repress transcription.[9]

Cell cycle suppression

Rb restricts the cell's ability to replicate DNA by preventing its progression from the G1 (first gap phase) to S (synthesis phase) phase of the cell division cycle.[10] Rb binds and inhibits E2 promoter-binding–protein-dimerization partner (E2F-DP) dimers, which are transcription factors of the E2F family that push the cell into S phase.[11][12][13][14][15][16] By keeping E2F-DP inactivated, RB1 maintains the cell in the G1 phase, preventing progression through the cell cycle and acting as a growth suppressor.[4] The Rb-E2F/DP complex also attracts a histone deacetylase (HDAC) protein to the chromatin, reducing transcription of S phase promoting factors, further suppressing DNA synthesis.

Activation and inactivation

See also: cyclin-dependent kinase and DREAM complex

When it is time for a cell to enter S phase, complexes of cyclin-dependent kinases (CDK) and cyclins phosphorylate Rb to pRb, allowing E2F-DP to dissociate from pRb and become active.[4] When E2F is free it activates factors like cyclins (e.g. cyclin E and cyclin A), which push the cell through the cell cycle by activating cyclin-dependent kinases, and a molecule called proliferating cell nuclear antigen, or PCNA, which speeds DNA replication and repair by helping to attach polymerase to DNA.[12][15][17][3][4][13][17][18] The initial phosphorylation is performed by Cyclin D/CDK4/CDK6, followed by additional phosphorylation by Cyclin E/CDK2. pRb remains phosphorylated throughout S, G2 and M phases.[4]

During the M-to-G1 transition, pRb is then progressively dephosphorylated by PP1, returning to its growth-suppressive hypophosphorylated state Rb.[4][19]

Rb family proteins are components of the DREAM complex (also named LINC complex), which is composed of LIN9, LIN54, LIN37, MYBL2, RBL1, RBL2, RBBP4, TFDP1, TFDP2, E2F4 and E2F5. There is a testis-specific version of the complex, where LIN54, MYBL2 and RBBP4 are replaced by MTL5, MYBL1 and RBBP7, respectively. In Drosophila both DREAM versions also exist, the components being mip130 (lin9 homolog, replaced by aly in testes), mip120 (lin54 homolog, replaced by tomb in testes), and Myb, Caf1p55, DP, Mip40, E2F2, Rbf and Rbf2. The DREAM complex exists in quiescent cells in association with MuvB (consisting of HDAC1 or HDAC2, LIN52 and L3mbtl1, L3mbtl3 or L3mbtl4) where it represses cell cycle-dependent genes. DREAM dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2.

Regeneration

Cochlea

The retinoblastoma protein is involved in the growth and development of mammalian hair cells of the cochlea, and appears to be related to the cells' inability to regenerate. Embryonic hair cells require Rb, among other important proteins, to exit the cell-cycle and stop dividing, which allows maturation of the auditory system. Once wild-type mammals have reached adulthood, their cochlear hair cells become incapable of proliferation. In studies where the gene for Rb is deleted in mice cochlea, hair cells continue to proliferate in early adulthood. Though this may seem to be a positive development, Rb-knockdown mice tend to develop severe hearing loss due to degeneration of the organ of Corti. For this reason, Rb seems to be instrumental for completing the development of mammalian hair cells and keeping them alive.[20][21] However, it is clear that without Rb, hair cells have the ability to proliferate, which is why Rb is known as a tumor suppressor. Temporarily and precisely turning off Rb in adult mammals with damaged hair cells may lead to propagation and therefore successful regeneration. Suppressing function of the retinoblastoma protein in the adult rat cochlea has been found to cause proliferation of supporting cells and hair cells. Rb can be downregulated by activating the sonic hedgehog pathway, which phosphorylates the proteins and reduces gene transcription.[22]

Neurons

Disrupting Rb expression in vitro, either by gene deletion or knockdown of Rb short interfering RNA, causes dendrites to branch out farther. In addition, Schwann cells, which provide essential support for the survival of neurons, travel with the neurites, extending farther than normal. The inhibition of Rb supports the continued growth of nerve cells.[23]

Interactions

Retinoblastoma protein has been shown to interact with:

Detection

Several methods for detecting the RB1 gene mutations have been developed[100] including a method that can detect large deletions that correlate with advanced stage retinoblastoma.[101]

Overview of signal transduction pathways involved in apoptosis.

See also

References

  1. ↑ Murphree AL, Benedict WF (March 1984). "Retinoblastoma: clues to human oncogenesis". Science. 223 (4640): 1028–33. doi:10.1126/science.6320372. PMID 6320372.
  2. ↑ Shao Z, Robbins PD (1995). "Differential regulation of E2F and Sp1-mediated transcription by G1 cyclins". Oncogene. 10 (2): 221–8. PMID 7838522.
  3. ↑ 3.0 3.1 Korenjak M, Brehm A (October 2005). "E2F-Rb complexes regulating transcription of genes important for differentiation and development". Current Opinion in Genetics & Development. 15 (5): 520–7. doi:10.1016/j.gde.2005.07.001. PMID 16081278.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Münger K, Howley PM (November 2002). "Human papillomavirus immortalization and transformation functions". Virus Res. 89 (2): 213–28. doi:10.1016/S0168-1702(02)00190-9. PMID 12445661.
  5. ↑ https://futurism.com/multicellular-life-caused-one-gene-gene-suppresses-cancer/
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