CUL4B: Difference between revisions

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{{Infobox_gene}}
{{PBB_Controls
Cullin-4B is a [[protein]] that in humans is encoded by the ''CUL4B'' [[gene]] which is located on the [[X chromosome]].<ref name="pmid8681378">{{cite journal | vauthors = Kipreos ET, Lander LE, Wing JP, He WW, Hedgecock EM | title = cul-1 is required for cell cycle exit in C. elegans and identifies a novel gene family | journal = Cell | volume = 85 | issue = 6 | pages = 829–39 | date = Aug 1996 | pmid = 8681378 | pmc =  | doi = 10.1016/S0092-8674(00)81267-2 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: CUL4B cullin 4B | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8450 }}</ref> '''CUL4B''' has high sequence similarity with [[CUL4A]], with which it shares certain E3 [[ubiquitin ligase]] functions. CUL4B is largely expressed in the nucleus and regulates several key functions including: [[cell cycle]] progression, [[chromatin remodeling]] and neurological and [[placenta]]l development in mice. In humans, ''CUL4B'' has been implicated in [[X-linked intellectual disability]] and is frequently mutated in [[pancreatic cancer|pancreatic adenocarcinomas]] and a small percentage of various lung cancers. Viruses such as [[HIV]] can also co-opt CUL4B-based complexes to promote [[viral pathogenesis]]. CUL4B complexes containing [[Cereblon]] are also targeted by the teratogenic drug [[thalidomide]].
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== Structure ==
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Human CUL4B is 913 amino acids long and shares a high degree of sequence identity (84%) with [[CUL4A]] with the exception of its unique N-terminal region.<ref name = "Fischer 2011">{{cite journal | vauthors = Fischer ES, Scrima A, Böhm K, Matsumoto S, Lingaraju GM, Faty M, Yasuda T, Cavadini S, Wakasugi M, Hanaoka F, Iwai S, Gut H, Sugasawa K, Thomä NH | title = The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture, targeting, and activation | journal = Cell | volume = 147 | issue = 5 | date = Nov 2011 | pmid = 22118460 | doi = 10.1016/j.cell.2011.10.035 | pages=1024–39}}</ref> The extreme N-terminus of CUL4B is disordered and, currently, it is unclear what structural and functional qualities it possesses. CUL4B binds to the beta-propeller of the DDB1 adaptor protein which interacts with numerous DDB1-CUL4-Associated Factors (DCAFs). This interaction is crucial for the recruitment of substrates to the ubiquitin ligase complex. At the C-terminal end, CUL4B interacts with the RBX1/ROC1 protein via its RING domain. RBX1 is a core component of Cullin-RING ubiquitin ligase (CRL) complexes and functions to recruit E2 ubiquitin conjugating enzymes. Therefore, the C-terminus of CUL4B - along with RBX1 and activated E2 enzymes - compose the catalytic core of CRL4B complexes. CUL4B is also modified by covalent attachment of a NEDD8 molecule at a highly conserved lysine residue in the C-terminal region. This modification appears to induce conformational changes which promotes flexibility in the RING domain of cullin proteins and enhanced ubiquitin ligase activity.<ref name = "Duda_2008">{{cite journal | vauthors = Duda DM, Borg LA, Scott DC, Hunt HW, Hammel M, Schulman BA | title = Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation | journal = Cell | volume = 134 | issue = 6 | date = Sep 2008 | pmid = 18805092 | doi = 10.1016/j.cell.2008.07.022 | pmc=2628631 | pages=995–1006}}</ref>
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== Functions ==
 
=== Cell cycle regulation and chromatin remodeling ===
 
CUL4B-based E3 ubiquitin ligase complexes often demonstrate overlapping activity with CUL4A-based complexes. Both CRL4 complexes utilize Cdt2 and the DNA [[processivity]] factor [[PCNA]] to induce the ubiquitination and degradation of [[DNA replication|replication]] licensing factor [[DNA replication factor CDT1|Cdt1]] and cyclin-dependent kinase inhibitor [[p21]] in a [[proteasome]]-dependent manner.<ref name = "Hu and Xiong 2006" /><ref name = "Nishitani 2008" /> CRL4<sup>Cdt2</sup> also degrades PCNA-bound [[SETD8|PR-Set7/SET8]], which is a histone 4 methyltransferase, and the p12 subunit of [[DNA polymerase delta|DNA polymerase δ]], which is crucial for DNA replication.<ref name = "Jorgensen_2011">{{cite journal | vauthors = Jørgensen S, Eskildsen M, Fugger K, Hansen L, Larsen MS, Kousholt AN, Syljuåsen RG, Trelle MB, Jensen ON, Helin K, Sørensen CS | title = SET8 is degraded via PCNA-coupled CRL4(CDT2) ubiquitylation in S phase and after UV irradiation | journal = The Journal of Cell Biology | volume = 192 | issue = 1 | pages = 43–54 | date = Jan 2011 | pmid = 21220508 | doi = 10.1083/jcb.201009076 | pmc=3019552}}</ref><ref name = "Zhang_2013">{{cite journal | vauthors = Zhang S, Zhao H, Darzynkiewicz Z, Zhou P, Zhang Z, Lee EY, Lee MY | title = A novel function of CRL4(Cdt2): regulation of the subunit structure of DNA polymerase δ in response to DNA damage and during the S phase | journal = The Journal of Biological Chemistry | volume = 288 | issue = 41 | pages = 29550–61 | date = Oct 2013 | pmid = 23913683 | doi = 10.1074/jbc.M113.490466 | pmc=3795253}}</ref> As a result, CRL4 complexes are able to control the onset of DNA replication, chromatin remodeling and progression through the cell cycle.
 
=== Mammalian embryonic development ===
 
Loss of ''Cul4b'' in mice causes embryonic lethality and defects in [[placenta]]l development. The extra-embryonic tissue of these developing mice also showed increased rates of [[apoptosis]] and a decrease in cell proliferation. When ''Cul4b'' deletion was limited to the [[epiblast]] (only in [[Sox2]]-expressing tissue), it was possible to generate living mice.<ref name = "Liu_2012">{{cite journal | vauthors = Liu L, Yin Y, Li Y, Prevedel L, Lacy EH, Ma L, Zhou P | title = Essential role of the CUL4B ubiquitin ligase in extra-embryonic tissue development during mouse embryogenesis | journal = Cell Research | volume = 22 | issue = 8 | date = Aug 2012 | pmid = 22453236 | doi = 10.1038/cr.2012.48 | pages=1258–69 | pmc=3411166}}</ref>
 
=== Neurological development ===
 
Mice that do not express CUL4B in epiblast tissue demonstrate normal brain morphology but decrease number of [[parvalbumin]] (PV)-positive GABAergic [[interneurons]] - particularly in the [[dentate gyrus]].<ref name = "Chen 2012">{{cite journal | vauthors = Chen CY, Tsai MS, Lin CY, Yu IS, Chen YT, Lin SR, Juan LW, Chen YT, Hsu HM, Lee LJ, Lin SW | title = Rescue of the genetically engineered Cul4b mutant mouse as a potential model for human X-linked mental retardation | journal = Human Molecular Genetics | volume = 21 | issue = 19 | date = Oct 2012 | pmid = 22763239 | doi = 10.1093/hmg/dds261 | pages=4270–85}}</ref> In these mice, certain dendritic features of [[hippocampus|hippocampal]] neurons were also affected by ''Cul4b'' loss, which may explain the observed increases in [[epilepsy|epilectic]] susceptibility and spatial learning defects. These [[phenotypes]] resembled features seen in patients with [[X-linked intellectual disability]] (see below).
 
== Clinical significance ==
 
=== X-linked intellectual disability ===
 
Loss-of-function ''CUL4B'' mutation events have been discovered in numerous patients with {{SWL|type=mutations_associated_to|target=X-linked intellectual disability|label=X-linked intellectual disability}}, which is characterized by aggressive outbursts, seizures, relative [[macrocephaly]], central obesity, [[hypogonadism]], [[pes cavus]] and tremor.<ref name="pmid24898194">{{cite journal | vauthors = Londin ER, Adijanto J, Philp N, Novelli A, Vitale E, Perria C, Serra G, Alesi V, Surrey S, Fortina P | title = Donor splice-site mutation in CUL4B is likely cause of X-linked intellectual disability | journal = Am. J. Med. Genet. A | volume = 164A | issue = 9 | pages = 2294–9 | year = 2014 | pmid = 24898194 | doi = 10.1002/ajmg.a.36629 }}</ref><ref name = "Zou 2007">{{cite journal | vauthors = Zou Y, Liu Q, Chen B, Zhang X, Guo C, Zhou H, Li J, Gao G, Guo Y, Yan C, Wei J, Shao C, Gong Y | title = Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation | journal = American Journal of Human Genetics | volume = 80 | issue = 3 | date = Mar 2007 | pmid = 17273978 | doi = 10.1086/512489 | pages=561–6 | pmc=1821105}}</ref><ref name = "Tarpey 2007">{{cite journal | vauthors = Tarpey PS, Raymond FL, O'Meara S, Edkins S, Teague J, Butler A, Dicks E, Stevens C, Tofts C, Avis T, Barthorpe S, Buck G, Cole J, Gray K, Halliday K, Harrison R, Hills K, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Varian J, West S, Widaa S, Mallya U, Moon J, Luo Y, Holder S, Smithson SF, Hurst JA, Clayton-Smith J, Kerr B, Boyle J, Shaw M, Vandeleur L, Rodriguez J, Slaugh R, Easton DF, Wooster R, Bobrow M, Srivastava AK, Stevenson RE, Schwartz CE, Turner G, Gecz J, Futreal PA, Stratton MR, Partington M | title = Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor | journal = American Journal of Human Genetics | volume = 80 | issue = 2 | date = Feb 2007 | pmid = 17236139 | doi = 10.1086/511134 | pages=345–52 | pmc=1785336}}</ref> ''CUL4B'' mutations have also been associated with malformations of cortical development.<ref name = "Vulto-van Silfhout 2015">{{cite journal | vauthors = Vulto-van Silfhout AT, Nakagawa T, Bahi-Buisson N, Haas SA, Hu H, Bienek M, Vissers LE, Gilissen C, Tzschach A, Busche A, Müsebeck J, Rump P, Mathijssen IB, Avela K, Somer M, Doagu F, Philips AK, Rauch A, Baumer A, Voesenek K, Poirier K, Vigneron J, Amram D, Odent S, Nawara M, Obersztyn E, Lenart J, Charzewska A, Lebrun N, Fischer U, Nillesen WM, Yntema HG, Järvelä I, Ropers HH, de Vries BB, Brunner HG, van Bokhoven H, Raymond FL, Willemsen MA, Chelly J, Xiong Y, Barkovich AJ, Kalscheuer VM, Kleefstra T, de Brouwer AP | title = Variants in CUL4B are associated with cerebral malformations | journal = Human Mutation | volume = 36 | issue = 1 | date = Jan 2015 | pmid = 25385192 | doi = 10.1002/humu.22718 | pages=106–17 | pmc=4608231}}</ref>
 
=== Viral pathogenesis ===
 
After HIV infects a cell, the virus "hijacks" either the CUL4B-DDB1 complex or the [[CUL4A|CUL4A-DDB1]] complex via the same mechanism. Essentially, HIV proteins such as [[Vpr]] and [[Vpx]] bind to [[VPRBP]] (a DDB1-binding substrate receptor protein) and induce the ubiquitination and degradation of [[SAMHD1]] and [[Uracil-DNA glycosylase|UNG2]] to promote viral replication.<ref name = "Sharifi 2014" /> These proteins are not degraded by CRL4 complexes in the absence of virus.
 
=== Cancer ===
 
According to data from [http://www.cbioportal.org/cross_cancer.do The Cancer Genome Atlas], ''CUL4B'' is mutated in 21% of pancreatic carcinomas with a recurring truncating mutation at amino acid 143. ''CUL4B'' is also mutated or amplified in 3-5% of lung cancers. The significance of these observed mutations has not been determined.
 
=== Thalidomide treatment ===
 
In 2010, Ito et al. reported that Cereblon, a DCAF protein, was a major target of the teratogenic compound thalidomide.<ref name = "Ito_2010">{{cite journal | vauthors = Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H | title = Identification of a primary target of thalidomide teratogenicity | journal = Science | volume = 327 | issue = 5971 | pages = 1345––50 | date = Mar 2010 | pmid = 20223979 | doi = 10.1126/science.1177319 }}</ref> Thalidomide and other derivatives such as [[pomalidomide]] and [[lenalidomide]] are known as [[immunomodulatory drug]]s (or IMiDs) and have been investigated as therapeutic agents for autoimmune diseases and several cancers - particularly myelomas. Recent reports show that IMiDs bind to CRL4<sup>CRBN</sup> and promote the degradation of IKZN1 and IKZN3 transcription factors, which are not normally targeted by CRL4 complexes.<ref name = "Lu_2014">{{cite journal | vauthors = Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, Wong KK, Bradner JE, Kaelin WG | title = The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins | journal = Science | volume = 343 | issue = 6168 | pages = 305–9 | date = Jan 2014 | pmid = 24292623 | doi = 10.1126/science.1244917 | pmc=4070318}}</ref><ref name = "Kronke_2014">{{cite journal | vauthors = Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X, Ciarlo C, Hartman E, Munshi N, Schenone M, Schreiber SL, Carr SA, Ebert BL | title = Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells | journal = Science | volume = 343 | issue = 6168 | pages = 301–5 | date = Jan 2014 | pmid = 24292625 | doi = 10.1126/science.1244851 | pmc=4077049}}</ref>
 
== Interactions and substrates ==
 
Human CUL4B forms direct [[Protein-protein interaction|interactions]] with:
* [[RBX1]]<ref name = "Ohta_1999">{{cite journal | vauthors = Ohta T, Michel JJ, Schottelius AJ, Xiong Y | title = ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity | journal = Molecular Cell | volume = 3 | issue = 4 | pages = 535–41 | date = Apr 1999 | pmid = 10230407 | doi=10.1016/s1097-2765(00)80482-7}}</ref>
* [[CAND1]]<ref name = pmid12609982>{{cite journal | vauthors = Min KW, Hwang JW, Lee JS, Park Y, Tamura TA, Yoon JB | title = TIP120A associates with cullins and modulates ubiquitin ligase activity | journal = J. Biol. Chem. | volume = 278 | issue = 18 | pages = 15905–10 | date = May 2003 | pmid = 12609982 | doi = 10.1074/jbc.M213070200 }}</ref>
* [[DDB1]]<ref name = pmid18593899>{{cite journal | vauthors = Guerrero-Santoro J, Kapetanaki MG, Hsieh CL, Gorbachinsky I, Levine AS, Rapić-Otrin V | title = The cullin 4B-based UV-damaged DNA-binding protein ligase binds to UV-damaged chromatin and ubiquitinates histone H2A | journal = Cancer Research | volume = 68 | issue = 13 | date = Jul 2008 | pmid = 18593899 | doi = 10.1158/0008-5472.CAN-07-6162 | pages=5014–22}}</ref>  and
* the [[COP9 signalosome]]<ref name = "Chew and Hagen 2007">{{cite journal | vauthors = Chew EH, Hagen T | title = Substrate-mediated regulation of cullin neddylation | journal = The Journal of Biological Chemistry | volume = 282 | issue = 23 | date = Jun 2007 | pmid = 17439941 | doi = 10.1074/jbc.M701153200 | pages=17032–40}}</ref>
 
Human CUL4B-DDB1-RBX1 complexes promote the ubiquitination of:
* [[DNA replication factor CDT1|Cdt1]]<ref name = "Hu and Xiong 2006">{{cite journal | vauthors = Hu J, Xiong Y | title = An evolutionarily conserved function of proliferating cell nuclear antigen for Cdt1 degradation by the Cul4-Ddb1 ubiquitin ligase in response to DNA damage | journal = The Journal of Biological Chemistry | volume = 281 | issue = 7 | date = Feb 2006 | pmid = 16407242 | doi = 10.1074/jbc.C500464200 | pages=3753–6}}</ref><ref name = "Nishitani 2006">{{cite journal | vauthors = Nishitani H, Sugimoto N, Roukos V, Nakanishi Y, Saijo M, Obuse C, Tsurimoto T, Nakayama KI, Nakayama K, Fujita M, Lygerou Z, Nishimoto T | title = Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis | journal = The EMBO Journal | volume = 25 | issue = 5 | date = Mar 2006 | pmid = 16482215 | doi = 10.1038/sj.emboj.7601002 | pages=1126–36 | pmc=1409712}}</ref>
* [[p21]]<ref name = "Nishitani 2008">{{cite journal | vauthors = Nishitani H, Shiomi Y, Iida H, Michishita M, Takami T, Tsurimoto T | title = CDK inhibitor p21 is degraded by a proliferating cell nuclear antigen-coupled Cul4-DDB1Cdt2 pathway during S phase and after UV irradiation | journal = The Journal of Biological Chemistry | volume = 283 | issue = 43 | date = Oct 2008 | pmid = 18703516 | doi = 10.1074/jbc.M806045200 | pages=29045–52 | pmc=2662008}}</ref><ref name = "Abbas 2008">{{cite journal | vauthors = Abbas T, Sivaprasad U, Terai K, Amador V, Pagano M, Dutta A | title = PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex | journal = Genes & Development | volume = 22 | issue = 18 | date = Sep 2008 | pmid = 18794347 | doi = 10.1101/gad.1676108 | pmc=2546691 | pages=2496–506}}</ref>
* [[SETD8|PR-Set7/SET8]]<ref name = "Jorgensen_2011" />
* [[DNA polymerase delta|p12 subunit of DNA polymerase δ]]<ref name = "Zhang_2013" />
* [[SAMHD1]]†<ref name = "Sharifi 2014">{{cite journal | vauthors = Sharifi HJ, Furuya AK, Jellinger RM, Nekorchuk MD, de Noronha CM | title = Cullin4A and cullin4B are interchangeable for HIV Vpr and Vpx action through the CRL4 ubiquitin ligase complex | journal = Journal of Virology | volume = 88 | issue = 12 | date = Jun 2014 | pmid = 24719410 | doi = 10.1128/JVI.00241-14 | pages=6944–58 | pmc=4054339}}</ref>
* [[Uracil-DNA glycosylase|UNG2]]†<ref name = "Sharifi 2014"/>
* [[IKZF1]]<sup>§</sup><ref name = "Lu_2014" /><ref name = "Kronke_2014" />
* [[IKZF3]]<sup>§</sup><ref name = "Lu_2014" /><ref name = "Kronke_2014" />
{{Div col end}}
<small><sup>†</sup>protein is a CRL4 substrate only when directed by viral proteins</small><br />
<small><sup>§</sup>protein is a CRL4 substrate only when directed by IMiDs</small>
 
==Notes==
{{Academic-written review
| wikidate = 2015
| journal = [[Gene (journal)|Gene]]
| title  = {{#property:P1476|from=Q28086765}}
| authors = {{#property:P2093|from=Q28086765}}
| date    = {{#property:P577|from=Q28086765}}
| volume  = {{#property:P478|from=Q28086765}}
| issue  = {{#property:P433|from=Q28086765}}
| pages  = {{#property:P304|from=Q28086765}}
| doi    = {{#property:P356|from=Q28086765}}
| pmid    = {{#property:P698|from=Q28086765}}
| pmc    = {{#property:P932|from=Q28086765}}
}}
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== References ==
{{GNF_Protein_box
{{reflist|33em}}
| image = PBB_Protein_CUL4B_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 2do7.
| PDB = {{PDB2|2do7}}
| Name = Cullin 4B
| HGNCid = 2555
| Symbol = CUL4B
| AltSymbols =; DKFZp686F1470; KIAA0695
| OMIM = 300304
| ECnumber = 
| Homologene = 2660
| MGIid = 1919834
| GeneAtlas_image1 = PBB_GE_CUL4B_202213_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_CUL4B_202214_s_at_tn.png
| GeneAtlas_image3 = PBB_GE_CUL4B_210257_x_at_tn.png
| Function = {{GNF_GO|id=GO:0003674 |text = molecular_function}} {{GNF_GO|id=GO:0005515 |text = protein binding}}
| Component = {{GNF_GO|id=GO:0005575 |text = cellular_component}}
| Process = {{GNF_GO|id=GO:0006281 |text = DNA repair}} {{GNF_GO|id=GO:0006512 |text = ubiquitin cycle}} {{GNF_GO|id=GO:0007049 |text = cell cycle}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 8450
    | Hs_Ensembl = ENSG00000158290
    | Hs_RefseqProtein = NP_001073341
    | Hs_RefseqmRNA = NM_001079872
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = X
    | Hs_GenLoc_start = 119542492
    | Hs_GenLoc_end = 119593677
    | Hs_Uniprot = Q13620
    | Mm_EntrezGene = 72584
    | Mm_Ensembl = ENSMUSG00000031095
    | Mm_RefseqmRNA = NM_028288
    | Mm_RefseqProtein = NP_082564
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = X
    | Mm_GenLoc_start = 34777901
    | Mm_GenLoc_end = 34820823
    | Mm_Uniprot = 
  }}
}}
'''Cullin 4B''', also known as '''CUL4B''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: CUL4B cullin 4B| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8450| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
==External links==
{{PBB_Summary
* {{UCSC gene info|CUL4B}}
| section_title =  
| summary_text = This gene is a member of the cullin family. The encoded protein forms a complex that functions as an E3 ubiquitin ligase and catalyzes the polyubiquitination of specific protein substrates in the cell. The protein interacts with a ring finger protein, and is required for the proteolysis of several regulators of DNA replication including chromatin licensing and DNA replication factor 1 and cyclin E. Multiple transcript variants encoding different isoforms have been found for this gene.<ref name="entrez">{{cite web | title = Entrez Gene: CUL4B cullin 4B| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8450| accessdate = }}</ref>
}}


==References==
== Further reading ==
{{reflist|2}}
{{refbegin|33em}}
==Further reading==
* {{cite journal | vauthors = Nakajima D, Okazaki N, Yamakawa H, Kikuno R, Ohara O, Nagase T | title = Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones | journal = DNA Res. | volume = 9 | issue = 3 | pages = 99–106 | year = 2003 | pmid = 12168954 | doi = 10.1093/dnares/9.3.99 }}
{{refbegin | 2}}
* {{cite journal | vauthors = Ishikawa K, Nagase T, Suyama M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O | title = Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro | journal = DNA Res. | volume = 5 | issue = 3 | pages = 169–76 | year = 1998 | pmid = 9734811 | doi = 10.1093/dnares/5.3.169 }}
{{PBB_Further_reading
* {{cite journal | vauthors = Wada H, Yeh ET, Kamitani T | title = Identification of NEDD8-conjugation site in human cullin-2 | journal = Biochem. Biophys. Res. Commun. | volume = 257 | issue = 1 | pages = 100–5 | year = 1999 | pmid = 10092517 | doi = 10.1006/bbrc.1999.0339 }}
| citations =
* {{cite journal | vauthors = Ohta T, Michel JJ, Schottelius AJ, Xiong Y | title = ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity | journal = Mol. Cell | volume = 3 | issue = 4 | pages = 535–41 | year = 1999 | pmid = 10230407 | doi = 10.1016/S1097-2765(00)80482-7 }}
*{{cite journal | author=Nakajima D, Okazaki N, Yamakawa H, ''et al.'' |title=Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones. |journal=DNA Res. |volume=9 |issue= 3 |pages= 99-106 |year= 2003 |pmid= 12168954 |doi= }}
* {{cite journal | vauthors = Hori T, Osaka F, Chiba T, Miyamoto C, Okabayashi K, Shimbara N, Kato S, Tanaka K | title = Covalent modification of all members of human cullin family proteins by NEDD8 | journal = Oncogene | volume = 18 | issue = 48 | pages = 6829–34 | year = 2000 | pmid = 10597293 | doi = 10.1038/sj.onc.1203093 }}
*{{cite journal  | author=Kipreos ET, Lander LE, Wing JP, ''et al.'' |title=cul-1 is required for cell cycle exit in C. elegans and identifies a novel gene family. |journal=Cell |volume=85 |issue= 6 |pages= 829-39 |year= 1996 |pmid= 8681378 |doi=  }}
* {{cite journal | vauthors = Jones EA, Clement-Jones M, Wilson DI | title = JAGGED1 expression in human embryos: correlation with the Alagille syndrome phenotype | journal = J. Med. Genet. | volume = 37 | issue = 9 | pages = 658–62 | year = 2000 | pmid = 10978356 | pmc = 1734694 | doi = 10.1136/jmg.37.9.658 }}
*{{cite journal | author=Ishikawa K, Nagase T, Suyama M, ''et al.'' |title=Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. |journal=DNA Res. |volume=5 |issue= 3 |pages= 169-76 |year= 1998 |pmid= 9734811 |doi= }}
* {{cite journal | vauthors = Zheng J, Yang X, Harrell JM, Ryzhikov S, Shim EH, Lykke-Andersen K, Wei N, Sun H, Kobayashi R, Zhang H | title = CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex | journal = Mol. Cell | volume = 10 | issue = 6 | pages = 1519–26 | year = 2003 | pmid = 12504026 | doi = 10.1016/S1097-2765(02)00784-0 }}
*{{cite journal | author=Wada H, Yeh ET, Kamitani T |title=Identification of NEDD8-conjugation site in human cullin-2. |journal=Biochem. Biophys. Res. Commun. |volume=257 |issue= 1 |pages= 100-5 |year= 1999 |pmid= 10092517 |doi= 10.1006/bbrc.1999.0339 }}
* {{cite journal | vauthors = Min KW, Hwang JW, Lee JS, Park Y, Tamura TA, Yoon JB | title = TIP120A associates with cullins and modulates ubiquitin ligase activity | journal = J. Biol. Chem. | volume = 278 | issue = 18 | pages = 15905–10 | year = 2003 | pmid = 12609982 | doi = 10.1074/jbc.M213070200 }}
*{{cite journal | author=Ohta T, Michel JJ, Schottelius AJ, Xiong Y |title=ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity. |journal=Mol. Cell |volume=3 |issue= 4 |pages= 535-41 |year= 1999 |pmid= 10230407 |doi= }}
* {{cite journal | vauthors = Higa LA, Mihaylov IS, Banks DP, Zheng J, Zhang H | title = Radiation-mediated proteolysis of CDT1 by CUL4-ROC1 and CSN complexes constitutes a new checkpoint | journal = Nat. Cell Biol. | volume = 5 | issue = 11 | pages = 1008–15 | year = 2004 | pmid = 14578910 | doi = 10.1038/ncb1061 }}
*{{cite journal | author=Hori T, Osaka F, Chiba T, ''et al.'' |title=Covalent modification of all members of human cullin family proteins by NEDD8. |journal=Oncogene |volume=18 |issue= 48 |pages= 6829-34 |year= 2000 |pmid= 10597293 |doi= 10.1038/sj.onc.1203093 }}
* {{cite journal | vauthors = Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP | title = Large-scale characterization of HeLa cell nuclear phosphoproteins | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 33 | pages = 12130–5 | year = 2004 | pmid = 15302935 | pmc = 514446 | doi = 10.1073/pnas.0404720101 }}
*{{cite journal | author=Jones EA, Clement-Jones M, Wilson DI |title=JAGGED1 expression in human embryos: correlation with the Alagille syndrome phenotype. |journal=J. Med. Genet. |volume=37 |issue= 9 |pages= 658-62 |year= 2000 |pmid= 10978356 |doi=  }}
* {{cite journal | vauthors = Higa LA, Yang X, Zheng J, Banks D, Wu M, Ghosh P, Sun H, Zhang H | title = Involvement of CUL4 ubiquitin E3 ligases in regulating CDK inhibitors Dacapo/p27Kip1 and cyclin E degradation | journal = Cell Cycle | volume = 5 | issue = 1 | pages = 71–7 | year = 2006 | pmid = 16322693 | doi = 10.4161/cc.5.1.2266 }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
* {{cite journal | vauthors = Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S | title = Diversification of transcriptional modulation: Large-scale identification and characterization of putative alternative promoters of human genes | journal = Genome Res. | volume = 16 | issue = 1 | pages = 55–65 | year = 2006 | pmid = 16344560 | pmc = 1356129 | doi = 10.1101/gr.4039406 }}
*{{cite journal | author=Zheng J, Yang X, Harrell JM, ''et al.'' |title=CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex. |journal=Mol. Cell |volume=10 |issue= 6 |pages= 1519-26 |year= 2003 |pmid= 12504026 |doi= }}
* {{cite journal | vauthors = Senga T, Sivaprasad U, Zhu W, Park JH, Arias EE, Walter JC, Dutta A | title = PCNA is a cofactor for Cdt1 degradation by CUL4/DDB1-mediated N-terminal ubiquitination | journal = J. Biol. Chem. | volume = 281 | issue = 10 | pages = 6246–52 | year = 2006 | pmid = 16407252 | doi = 10.1074/jbc.M512705200 }}
*{{cite journal | author=Min KW, Hwang JW, Lee JS, ''et al.'' |title=TIP120A associates with cullins and modulates ubiquitin ligase activity. |journal=J. Biol. Chem. |volume=278 |issue= 18 |pages= 15905-10 |year= 2003 |pmid= 12609982 |doi= 10.1074/jbc.M213070200 }}
* {{cite journal | vauthors = Li T, Santockyte R, Shen RF, Tekle E, Wang G, Yang DC, Chock PB | title = A general approach for investigating enzymatic pathways and substrates for ubiquitin-like modifiers | journal = Arch. Biochem. Biophys. | volume = 453 | issue = 1 | pages = 70–4 | year = 2006 | pmid = 16620772 | doi = 10.1016/j.abb.2006.03.002 }}
*{{cite journal | author=Higa LA, Mihaylov IS, Banks DP, ''et al.'' |title=Radiation-mediated proteolysis of CDT1 by CUL4-ROC1 and CSN complexes constitutes a new checkpoint. |journal=Nat. Cell Biol. |volume=5 |issue= 11 |pages= 1008-15 |year= 2004 |pmid= 14578910 |doi= 10.1038/ncb1061 }}
* {{cite journal | vauthors = Wang H, Zhai L, Xu J, Joo HY, Jackson S, Erdjument-Bromage H, Tempst P, Xiong Y, Zhang Y | title = Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage | journal = Mol. Cell | volume = 22 | issue = 3 | pages = 383–94 | year = 2006 | pmid = 16678110 | doi = 10.1016/j.molcel.2006.03.035 }}
*{{cite journal | author=Beausoleil SA, Jedrychowski M, Schwartz D, ''et al.'' |title=Large-scale characterization of HeLa cell nuclear phosphoproteins. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue= 33 |pages= 12130-5 |year= 2004 |pmid= 15302935 |doi= 10.1073/pnas.0404720101 }}
*{{cite journal | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
*{{cite journal  | author=Ross MT, Grafham DV, Coffey AJ, ''et al.'' |title=The DNA sequence of the human X chromosome. |journal=Nature |volume=434 |issue= 7031 |pages= 325-37 |year= 2005 |pmid= 15772651 |doi= 10.1038/nature03440 }}
*{{cite journal  | author=Higa LA, Yang X, Zheng J, ''et al.'' |title=Involvement of CUL4 ubiquitin E3 ligases in regulating CDK inhibitors Dacapo/p27Kip1 and cyclin E degradation. |journal=Cell Cycle |volume=5 |issue= 1 |pages= 71-7 |year= 2006 |pmid= 16322693 |doi= }}
*{{cite journal | author=Kimura K, Wakamatsu A, Suzuki Y, ''et al.'' |title=Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. |journal=Genome Res. |volume=16 |issue= 1 |pages= 55-65 |year= 2006 |pmid= 16344560 |doi= 10.1101/gr.4039406 }}
*{{cite journal | author=Senga T, Sivaprasad U, Zhu W, ''et al.'' |title=PCNA is a cofactor for Cdt1 degradation by CUL4/DDB1-mediated N-terminal ubiquitination. |journal=J. Biol. Chem. |volume=281 |issue= 10 |pages= 6246-52 |year= 2006 |pmid= 16407252 |doi= 10.1074/jbc.M512705200 }}
*{{cite journal | author=Li T, Santockyte R, Shen RF, ''et al.'' |title=A general approach for investigating enzymatic pathways and substrates for ubiquitin-like modifiers. |journal=Arch. Biochem. Biophys. |volume=453 |issue= 1 |pages= 70-4 |year= 2006 |pmid= 16620772 |doi= 10.1016/j.abb.2006.03.002 }}
*{{cite journal | author=Wang H, Zhai L, Xu J, ''et al.'' |title=Histone H3 and H4 ubiquitylation by the CUL4-DDB-ROC1 ubiquitin ligase facilitates cellular response to DNA damage. |journal=Mol. Cell |volume=22 |issue= 3 |pages= 383-94 |year= 2006 |pmid= 16678110 |doi= 10.1016/j.molcel.2006.03.035 }}
}}
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{{refend}}


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Revision as of 16:48, 2 October 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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View/Edit Human

Cullin-4B is a protein that in humans is encoded by the CUL4B gene which is located on the X chromosome.[1][2] CUL4B has high sequence similarity with CUL4A, with which it shares certain E3 ubiquitin ligase functions. CUL4B is largely expressed in the nucleus and regulates several key functions including: cell cycle progression, chromatin remodeling and neurological and placental development in mice. In humans, CUL4B has been implicated in X-linked intellectual disability and is frequently mutated in pancreatic adenocarcinomas and a small percentage of various lung cancers. Viruses such as HIV can also co-opt CUL4B-based complexes to promote viral pathogenesis. CUL4B complexes containing Cereblon are also targeted by the teratogenic drug thalidomide.

Structure

Human CUL4B is 913 amino acids long and shares a high degree of sequence identity (84%) with CUL4A with the exception of its unique N-terminal region.[3] The extreme N-terminus of CUL4B is disordered and, currently, it is unclear what structural and functional qualities it possesses. CUL4B binds to the beta-propeller of the DDB1 adaptor protein which interacts with numerous DDB1-CUL4-Associated Factors (DCAFs). This interaction is crucial for the recruitment of substrates to the ubiquitin ligase complex. At the C-terminal end, CUL4B interacts with the RBX1/ROC1 protein via its RING domain. RBX1 is a core component of Cullin-RING ubiquitin ligase (CRL) complexes and functions to recruit E2 ubiquitin conjugating enzymes. Therefore, the C-terminus of CUL4B - along with RBX1 and activated E2 enzymes - compose the catalytic core of CRL4B complexes. CUL4B is also modified by covalent attachment of a NEDD8 molecule at a highly conserved lysine residue in the C-terminal region. This modification appears to induce conformational changes which promotes flexibility in the RING domain of cullin proteins and enhanced ubiquitin ligase activity.[4]

Functions

Cell cycle regulation and chromatin remodeling

CUL4B-based E3 ubiquitin ligase complexes often demonstrate overlapping activity with CUL4A-based complexes. Both CRL4 complexes utilize Cdt2 and the DNA processivity factor PCNA to induce the ubiquitination and degradation of replication licensing factor Cdt1 and cyclin-dependent kinase inhibitor p21 in a proteasome-dependent manner.[5][6] CRL4Cdt2 also degrades PCNA-bound PR-Set7/SET8, which is a histone 4 methyltransferase, and the p12 subunit of DNA polymerase δ, which is crucial for DNA replication.[7][8] As a result, CRL4 complexes are able to control the onset of DNA replication, chromatin remodeling and progression through the cell cycle.

Mammalian embryonic development

Loss of Cul4b in mice causes embryonic lethality and defects in placental development. The extra-embryonic tissue of these developing mice also showed increased rates of apoptosis and a decrease in cell proliferation. When Cul4b deletion was limited to the epiblast (only in Sox2-expressing tissue), it was possible to generate living mice.[9]

Neurological development

Mice that do not express CUL4B in epiblast tissue demonstrate normal brain morphology but decrease number of parvalbumin (PV)-positive GABAergic interneurons - particularly in the dentate gyrus.[10] In these mice, certain dendritic features of hippocampal neurons were also affected by Cul4b loss, which may explain the observed increases in epilectic susceptibility and spatial learning defects. These phenotypes resembled features seen in patients with X-linked intellectual disability (see below).

Clinical significance

X-linked intellectual disability

Loss-of-function CUL4B mutation events have been discovered in numerous patients with X-linked intellectual disability , which is characterized by aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus and tremor.[11][12][13] CUL4B mutations have also been associated with malformations of cortical development.[14]

Viral pathogenesis

After HIV infects a cell, the virus "hijacks" either the CUL4B-DDB1 complex or the CUL4A-DDB1 complex via the same mechanism. Essentially, HIV proteins such as Vpr and Vpx bind to VPRBP (a DDB1-binding substrate receptor protein) and induce the ubiquitination and degradation of SAMHD1 and UNG2 to promote viral replication.[15] These proteins are not degraded by CRL4 complexes in the absence of virus.

Cancer

According to data from The Cancer Genome Atlas, CUL4B is mutated in 21% of pancreatic carcinomas with a recurring truncating mutation at amino acid 143. CUL4B is also mutated or amplified in 3-5% of lung cancers. The significance of these observed mutations has not been determined.

Thalidomide treatment

In 2010, Ito et al. reported that Cereblon, a DCAF protein, was a major target of the teratogenic compound thalidomide.[16] Thalidomide and other derivatives such as pomalidomide and lenalidomide are known as immunomodulatory drugs (or IMiDs) and have been investigated as therapeutic agents for autoimmune diseases and several cancers - particularly myelomas. Recent reports show that IMiDs bind to CRL4CRBN and promote the degradation of IKZN1 and IKZN3 transcription factors, which are not normally targeted by CRL4 complexes.[17][18]

Interactions and substrates

Human CUL4B forms direct interactions with:

Human CUL4B-DDB1-RBX1 complexes promote the ubiquitination of:

†protein is a CRL4 substrate only when directed by viral proteins
§protein is a CRL4 substrate only when directed by IMiDs

Notes


References

  1. ↑ Kipreos ET, Lander LE, Wing JP, He WW, Hedgecock EM (Aug 1996). "cul-1 is required for cell cycle exit in C. elegans and identifies a novel gene family". Cell. 85 (6): 829–39. doi:10.1016/S0092-8674(00)81267-2. PMID 8681378.
  2. ↑ "Entrez Gene: CUL4B cullin 4B".
  3. ↑ Fischer ES, Scrima A, Böhm K, Matsumoto S, Lingaraju GM, Faty M, Yasuda T, Cavadini S, Wakasugi M, Hanaoka F, Iwai S, Gut H, Sugasawa K, Thomä NH (Nov 2011). "The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture, targeting, and activation". Cell. 147 (5): 1024–39. doi:10.1016/j.cell.2011.10.035. PMID 22118460.
  4. ↑ Duda DM, Borg LA, Scott DC, Hunt HW, Hammel M, Schulman BA (Sep 2008). "Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation". Cell. 134 (6): 995–1006. doi:10.1016/j.cell.2008.07.022. PMC 2628631. PMID 18805092.
  5. ↑ 5.0 5.1 Hu J, Xiong Y (Feb 2006). "An evolutionarily conserved function of proliferating cell nuclear antigen for Cdt1 degradation by the Cul4-Ddb1 ubiquitin ligase in response to DNA damage". The Journal of Biological Chemistry. 281 (7): 3753–6. doi:10.1074/jbc.C500464200. PMID 16407242.
  6. ↑ 6.0 6.1 Nishitani H, Shiomi Y, Iida H, Michishita M, Takami T, Tsurimoto T (Oct 2008). "CDK inhibitor p21 is degraded by a proliferating cell nuclear antigen-coupled Cul4-DDB1Cdt2 pathway during S phase and after UV irradiation". The Journal of Biological Chemistry. 283 (43): 29045–52. doi:10.1074/jbc.M806045200. PMC 2662008. PMID 18703516.
  7. ↑ 7.0 7.1 Jørgensen S, Eskildsen M, Fugger K, Hansen L, Larsen MS, Kousholt AN, Syljuåsen RG, Trelle MB, Jensen ON, Helin K, Sørensen CS (Jan 2011). "SET8 is degraded via PCNA-coupled CRL4(CDT2) ubiquitylation in S phase and after UV irradiation". The Journal of Cell Biology. 192 (1): 43–54. doi:10.1083/jcb.201009076. PMC 3019552. PMID 21220508.
  8. ↑ 8.0 8.1 Zhang S, Zhao H, Darzynkiewicz Z, Zhou P, Zhang Z, Lee EY, Lee MY (Oct 2013). "A novel function of CRL4(Cdt2): regulation of the subunit structure of DNA polymerase δ in response to DNA damage and during the S phase". The Journal of Biological Chemistry. 288 (41): 29550–61. doi:10.1074/jbc.M113.490466. PMC 3795253. PMID 23913683.
  9. ↑ Liu L, Yin Y, Li Y, Prevedel L, Lacy EH, Ma L, Zhou P (Aug 2012). "Essential role of the CUL4B ubiquitin ligase in extra-embryonic tissue development during mouse embryogenesis". Cell Research. 22 (8): 1258–69. doi:10.1038/cr.2012.48. PMC 3411166. PMID 22453236.
  10. ↑ Chen CY, Tsai MS, Lin CY, Yu IS, Chen YT, Lin SR, Juan LW, Chen YT, Hsu HM, Lee LJ, Lin SW (Oct 2012). "Rescue of the genetically engineered Cul4b mutant mouse as a potential model for human X-linked mental retardation". Human Molecular Genetics. 21 (19): 4270–85. doi:10.1093/hmg/dds261. PMID 22763239.
  11. ↑ Londin ER, Adijanto J, Philp N, Novelli A, Vitale E, Perria C, Serra G, Alesi V, Surrey S, Fortina P (2014). "Donor splice-site mutation in CUL4B is likely cause of X-linked intellectual disability". Am. J. Med. Genet. A. 164A (9): 2294–9. doi:10.1002/ajmg.a.36629. PMID 24898194.
  12. ↑ Zou Y, Liu Q, Chen B, Zhang X, Guo C, Zhou H, Li J, Gao G, Guo Y, Yan C, Wei J, Shao C, Gong Y (Mar 2007). "Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation". American Journal of Human Genetics. 80 (3): 561–6. doi:10.1086/512489. PMC 1821105. PMID 17273978.
  13. ↑ Tarpey PS, Raymond FL, O'Meara S, Edkins S, Teague J, Butler A, Dicks E, Stevens C, Tofts C, Avis T, Barthorpe S, Buck G, Cole J, Gray K, Halliday K, Harrison R, Hills K, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Varian J, West S, Widaa S, Mallya U, Moon J, Luo Y, Holder S, Smithson SF, Hurst JA, Clayton-Smith J, Kerr B, Boyle J, Shaw M, Vandeleur L, Rodriguez J, Slaugh R, Easton DF, Wooster R, Bobrow M, Srivastava AK, Stevenson RE, Schwartz CE, Turner G, Gecz J, Futreal PA, Stratton MR, Partington M (Feb 2007). "Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor". American Journal of Human Genetics. 80 (2): 345–52. doi:10.1086/511134. PMC 1785336. PMID 17236139.
  14. ↑ Vulto-van Silfhout AT, Nakagawa T, Bahi-Buisson N, Haas SA, Hu H, Bienek M, Vissers LE, Gilissen C, Tzschach A, Busche A, Müsebeck J, Rump P, Mathijssen IB, Avela K, Somer M, Doagu F, Philips AK, Rauch A, Baumer A, Voesenek K, Poirier K, Vigneron J, Amram D, Odent S, Nawara M, Obersztyn E, Lenart J, Charzewska A, Lebrun N, Fischer U, Nillesen WM, Yntema HG, Järvelä I, Ropers HH, de Vries BB, Brunner HG, van Bokhoven H, Raymond FL, Willemsen MA, Chelly J, Xiong Y, Barkovich AJ, Kalscheuer VM, Kleefstra T, de Brouwer AP (Jan 2015). "Variants in CUL4B are associated with cerebral malformations". Human Mutation. 36 (1): 106–17. doi:10.1002/humu.22718. PMC 4608231. PMID 25385192.
  15. ↑ 15.0 15.1 15.2 Sharifi HJ, Furuya AK, Jellinger RM, Nekorchuk MD, de Noronha CM (Jun 2014). "Cullin4A and cullin4B are interchangeable for HIV Vpr and Vpx action through the CRL4 ubiquitin ligase complex". Journal of Virology. 88 (12): 6944–58. doi:10.1128/JVI.00241-14. PMC 4054339. PMID 24719410.
  16. ↑ Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H (Mar 2010). "Identification of a primary target of thalidomide teratogenicity". Science. 327 (5971): 1345––50. doi:10.1126/science.1177319. PMID 20223979.
  17. ↑ 17.0 17.1 17.2 Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, Wong KK, Bradner JE, Kaelin WG (Jan 2014). "The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins". Science. 343 (6168): 305–9. doi:10.1126/science.1244917. PMC 4070318. PMID 24292623.
  18. ↑ 18.0 18.1 18.2 Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X, Ciarlo C, Hartman E, Munshi N, Schenone M, Schreiber SL, Carr SA, Ebert BL (Jan 2014). "Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells". Science. 343 (6168): 301–5. doi:10.1126/science.1244851. PMC 4077049. PMID 24292625.
  19. ↑ Ohta T, Michel JJ, Schottelius AJ, Xiong Y (Apr 1999). "ROC1, a homolog of APC11, represents a family of cullin partners with an associated ubiquitin ligase activity". Molecular Cell. 3 (4): 535–41. doi:10.1016/s1097-2765(00)80482-7. PMID 10230407.
  20. ↑ Min KW, Hwang JW, Lee JS, Park Y, Tamura TA, Yoon JB (May 2003). "TIP120A associates with cullins and modulates ubiquitin ligase activity". J. Biol. Chem. 278 (18): 15905–10. doi:10.1074/jbc.M213070200. PMID 12609982.
  21. ↑ Guerrero-Santoro J, Kapetanaki MG, Hsieh CL, Gorbachinsky I, Levine AS, Rapić-Otrin V (Jul 2008). "The cullin 4B-based UV-damaged DNA-binding protein ligase binds to UV-damaged chromatin and ubiquitinates histone H2A". Cancer Research. 68 (13): 5014–22. doi:10.1158/0008-5472.CAN-07-6162. PMID 18593899.
  22. ↑ Chew EH, Hagen T (Jun 2007). "Substrate-mediated regulation of cullin neddylation". The Journal of Biological Chemistry. 282 (23): 17032–40. doi:10.1074/jbc.M701153200. PMID 17439941.
  23. ↑ Nishitani H, Sugimoto N, Roukos V, Nakanishi Y, Saijo M, Obuse C, Tsurimoto T, Nakayama KI, Nakayama K, Fujita M, Lygerou Z, Nishimoto T (Mar 2006). "Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis". The EMBO Journal. 25 (5): 1126–36. doi:10.1038/sj.emboj.7601002. PMC 1409712. PMID 16482215.
  24. ↑ Abbas T, Sivaprasad U, Terai K, Amador V, Pagano M, Dutta A (Sep 2008). "PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex". Genes & Development. 22 (18): 2496–506. doi:10.1101/gad.1676108. PMC 2546691. PMID 18794347.

External links

Further reading

Retrieved from "https://www.wikidoc.org/index.php?title=CUL4B&oldid=1423024"