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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox gene}}
{{PBB_Controls
'''Paired box gene 8''', also known as '''PAX8''', is a [[protein]] which in humans is encoded by the ''PAX8'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: PAX8 paired box gene 8| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7849| accessdate = }}</ref>
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
}}


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
This gene is a member of the paired box ([[pax genes|PAX]]) family of [[transcription factor]]s. Members of this gene family typically encode proteins which contain a [[paired box domain]], an octapeptide, and a paired-type [[homeodomain fold|homeodomain]]. The PAX gene family has an important role in the formation of tissues and organs during embryonic development and maintaining the normal function of some cells after birth.  The PAX genes give instructions for making proteins that attach themselves to certain areas of DNA.<ref>{{Cite web|url=https://ghr.nlm.nih.gov/gene/PAX8|title=PAX8 gene|date=2016-03-28|website=Genetics Home Reference|access-date=2016-04-05}}</ref> This nuclear protein is involved in [[thyroid epithelial cell|thyroid follicular cell]] development and expression of thyroid-specific genes. PAX8 releases the hormones important for regulating growth, brain development, and metabolism. Also functions in very early stages of kidney organogenesis, the müllerian system, and the thymus.<ref>{{cite journal | vauthors = Laury AR, Perets R, Piao H, Krane JF, Barletta JA, French C, Chirieac LR, Lis R, Loda M, Hornick JL, Drapkin R, Hirsch MS | title = A comprehensive analysis of PAX8 expression in human epithelial tumors | journal = The American Journal of Surgical Pathology | volume = 35 | issue = 6 | pages = 816–26 | date = June 2011 | pmid = 21552115 | doi = 10.1097/PAS.0b013e318216c112 }}</ref> Additionally, PAX8 is expressed in the renal excretory system, epithelial cells of the endocervix, endometrium, ovary, Fallopian tube, seminal vesicle, epididymis, pancreatic islet cells and lymphoid cells.<ref name="Fernández_2015">{{cite journal | vauthors = Fernández LP, López-Márquez A, Santisteban P | title = Thyroid transcription factors in development, differentiation and disease | journal = Nature Reviews. Endocrinology | volume = 11 | issue = 1 | pages = 29–42 | date = January 2015 | pmid = 25350068 | doi = 10.1038/nrendo.2014.186 }}</ref> PAX8 and other transcription factors play a role in binding to DNA and regulating the genes that drive thyroid hormone synthesis (Tg, TPO, Slc5a5 and Tshr).
| image = PBB_Protein_PAX8_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1k78.
| PDB = {{PDB2|1k78}}, {{PDB2|1mdm}}
  | Name = Paired box gene 8
| HGNCid = 8622
| Symbol = PAX8
| AltSymbols =;
| OMIM = 167415
| ECnumber = 
| Homologene = 2589
| MGIid = 97492
| GeneAtlas_image1 = PBB_GE_PAX8_121_at_tn.png
  | GeneAtlas_image2 = PBB_GE_PAX8_207921_x_at_tn.png
| GeneAtlas_image3 = PBB_GE_PAX8_207923_x_at_tn.png
| Function = {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0004550 |text = nucleoside diphosphate kinase activity}} {{GNF_GO|id=GO:0004996 |text = thyroid-stimulating hormone receptor activity}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005524 |text = ATP binding}} {{GNF_GO|id=GO:0016563 |text = transcription activator activity}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005654 |text = nucleoplasm}}
| Process = {{GNF_GO|id=GO:0006183 |text = GTP biosynthetic process}} {{GNF_GO|id=GO:0006228 |text = UTP biosynthetic process}} {{GNF_GO|id=GO:0006241 |text = CTP biosynthetic process}} {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0007275 |text = multicellular organismal development}} {{GNF_GO|id=GO:0009653 |text = anatomical structure morphogenesis}} {{GNF_GO|id=GO:0030154 |text = cell differentiation}} {{GNF_GO|id=GO:0045893 |text = positive regulation of transcription, DNA-dependent}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 7849
    | Hs_Ensembl = ENSG00000125618
    | Hs_RefseqProtein = NP_003457
    | Hs_RefseqmRNA = NM_003466
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 2
    | Hs_GenLoc_start = 113690046
    | Hs_GenLoc_end = 113720991
    | Hs_Uniprot = Q06710
    | Mm_EntrezGene = 18510
    | Mm_Ensembl = ENSMUSG00000026976
    | Mm_RefseqmRNA = NM_011040
    | Mm_RefseqProtein = NP_035170
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 2
    | Mm_GenLoc_start = 24242560
    | Mm_GenLoc_end = 24297608
    | Mm_Uniprot = Q6GU20
  }}
}}
'''Paired box gene 8''', also known as '''PAX8''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: PAX8 paired box gene 8| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7849| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
PAX8 (and PAX2) is one of the important regulators of urogenital system morphogenesis.  They play a role in the specification of the first renal cells of the embryo and remain essential players throughout development.<ref name=":1">{{cite journal | vauthors = Sharma R, Sanchez-Ferras O, Bouchard M | title = Pax genes in renal development, disease and regeneration | journal = Seminars in Cell & Developmental Biology | volume = 44 | pages = 97–106 | date = August 2015 | pmid = 26410163 | doi = 10.1016/j.semcdb.2015.09.016 | url = http://www.sciencedirect.com/science/article/pii/S1084952115001767 | series = Paramutation & Pax Transcription Factors }}</ref>
{{PBB_Summary
| section_title =
| summary_text = This gene is a member of the paired box (PAX) family of transcription factors. Members of this gene family typically encode proteins which contain a paired box domain, an octapeptide, and a paired-type homeodomain. This nuclear protein is involved in thyroid follicular cell development and expression of thyroid-specific genes. Mutations in this gene have been associated with thyroid dysgenesis, thyroid follicular carcinomas and atypical follicular thyroid adenomas. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.<ref name="entrez">{{cite web | title = Entrez Gene: PAX8 paired box gene 8| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7849| accessdate = }}</ref>
}}


==See also==
==Clinical significance==
Mutations  in this gene have been associated with [[thyroid dysgenesis]], [[follicular thyroid cancer|thyroid follicular carcinoma]]s and atypical follicular [[thyroid adenoma]]s. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.<ref name="entrez"/>
 
The PAX8 gene is also associated congenital hypothyroidism due to thyroid dysgenesis because of its role in growth and development of the thyroid gland. A mutation in the PAX8 gene could prevent or disrupt normal development.  These mutations can affect different functions of the protein including DNA biding, gene activation, protein stability, and cooperation with the co-activator p300. PAX gene deficiencies can result in development defects called Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
 
=== Cancer ===
PAX8 is considered a "master regulator transcription factor".<ref name="Fernández_2015" /> As a master regulator, it is possible that it regulates expression of genes other than thyroid-specific.  Several known tumor suppressor genes like TP53 and WT1 have been identified as transcriptional targets in human astrocytoma cells.  Over 90% of thyroid tumors arise from follicular thyroid cells.<ref name="Fernández_2015" />  A fusion protein, ''PAX8-PPAR-γ'', is implicated in some follicular thyroid carcinomas and follicular-variant papillary thyroid carcinoma.<ref>{{cite journal | vauthors = Raman P, Koenig RJ | title = Pax-8-PPAR-γ fusion protein in thyroid carcinoma | journal = Nature Reviews. Endocrinology | volume = 10 | issue = 10 | pages = 616–23 | date = October 2014 | pmid = 25069464 | doi = 10.1038/nrendo.2014.115 | pmc=4290886}}</ref>  The mechanism for this transformation is not well understood, but there are several proposed possibilities.<ref>{{cite journal | vauthors = Rüsch A, Erway LC, Oliver D, Vennström B, Forrest D | title = Thyroid hormone receptor beta-dependent expression of a potassium conductance in inner hair cells at the onset of hearing | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 26 | pages = 15758–62 | date = December 1998 | pmid = 9861043 | pmc = 28117 | doi=10.1073/pnas.95.26.15758}}</ref><ref>{{cite journal | vauthors = Weiss RE, Xu J, Ning G, Pohlenz J, O'Malley BW, Refetoff S | title = Mice deficient in the steroid receptor co-activator 1 (SRC-1) are resistant to thyroid hormone | journal = The EMBO Journal | volume = 18 | issue = 7 | pages = 1900–4 | date = April 1999 | pmid = 10202153 | pmc = 1171275 | doi = 10.1093/emboj/18.7.1900 }}</ref><ref>{{cite journal | vauthors = Brown NS, Smart A, Sharma V, Brinkmeier ML, Greenlee L, Camper SA, Jensen DR, Eckel RH, Krezel W, Chambon P, Haugen BR | title = Thyroid hormone resistance and increased metabolic rate in the RXR-gamma-deficient mouse | journal = The Journal of Clinical Investigation | volume = 106 | issue = 1 | pages = 73–9 | date = July 2000 | pmid = 10880050 | pmc = 314362 | doi = 10.1172/JCI9422 }}</ref>
* Inhibition of normal PPAR y function by chimeric PAX8/PPARy protein through a dominant negative effect
* Activation of normal PPARy targets due to the over expression of the chimeric protein that contain all functional domains of wild-type PPAR y
* Deregulation of PAX8 function
* Activation of a set of genes unrelated to both wild-type PPARy and wild-type PAX8 pathways 
The PAX 8 gene has some association with follicular thyroid tumors. ''PAX8/PPARy'' rearrangement account for 30-40% of conventional type follicular carcinomas<ref>{{cite journal | vauthors = Nikiforova MN, Lynch RA, Biddinger PW, Alexander EK, Dorn GW, Tallini G, Kroll TG, Nikiforov YE | title = RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 88 | issue = 5 | pages = 2318–26 | date = May 2003 | pmid = 12727991 | doi = 10.1210/jc.2002-021907 }}</ref> and less than 5% of oncocytic carcinomas (aka Hurthle-Cell Neoplasms).<ref>{{cite journal | vauthors = Abel ED, Boers ME, Pazos-Moura C, Moura E, Kaulbach H, Zakaria M, Lowell B, Radovick S, Liberman MC, Wondisford F | title = Divergent roles for thyroid hormone receptor beta isoforms in the endocrine axis and auditory system | journal = The Journal of Clinical Investigation | volume = 104 | issue = 3 | pages = 291–300 | date = August 1999 | pmid = 10430610 | pmc = 408418 | doi = 10.1172/JCI6397 }}</ref>  Tumors expressing the ''PAX8/PPARy'' are usually present in at a young age, small in size, present in a solid/nested growth pattern and frequently involve vascular invasion.  It has been observed that ''PAX8/PPAR y''-positive tumors rarely express ''RAS'' mutations in combination.  This suggests that follicular carcinomas develop in two distinct pathways either with ''PAX8/PPAR y'' or ''RAS''.
 
Some whole-genome sequencing studies have shown that PAX8 also targets BRCA1 (carcinogenesis), MAPK pathways (thyroid malignancies), and Ccnb1 and Ccnb2 (cell-cycle processes).  PAX8 is shown to be involved in tumor cell proliferation and differentiation, signal transduction, apoptosis, cell polarity and transport, cell motility and adhesion.<ref name="Fernández_2015" />
 
Expression of PAX8 is increased in neoplastic renal tissues, Wilms tumors, ovarian cancer and Müllerian carcinomas.  For this reason, the immunodetection of PAX8 is widely used for diagnosing primary and metastatic renal tumors.  Re-activation of PAX8 (or Pax2) expression has been reported in pediatric Wilms Tumors, almost all subtypes of renal cell carcinoma, nephrogenic adenomas, ovarian cancer cells, bladder, prostate, and endometrial carcinomas.<ref name=":1" />  The mechanism of switching on the genes is unknown.  Some studies have suggested that the renal PAX genes act as pro-survival factors and allow tumor cells to resist apoptosis.  Down regulation of the PAX gene expression inhibits cell growth and induces apoptosis.  This could be a possible avenue for therapeutic targets in renal cancer.
 
== Interactions ==
PAX8 has been shown to [[Protein-protein interaction|interact]] with [[NK2 homeobox 1]].<ref name=pmid12441357>{{cite journal | vauthors = Di Palma T, Nitsch R, Mascia A, Nitsch L, Di Lauro R, Zannini M | title = The paired domain-containing factor Pax8 and the homeodomain-containing factor TTF-1 directly interact and synergistically activate transcription | journal = The Journal of Biological Chemistry | volume = 278 | issue = 5 | pages = 3395–402 | date = January 2003 | pmid = 12441357 | doi = 10.1074/jbc.M205977200 }}</ref>
 
== See also ==
* [[Pax genes]]
* [[Pax genes]]


==References==
== References ==
{{reflist|2}}
{{reflist|33em}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin|33em}}
{{PBB_Further_reading
* {{cite journal | vauthors = Poleev A, Fickenscher H, Mundlos S, Winterpacht A, Zabel B, Fidler A, Gruss P, Plachov D | title = PAX8, a human paired box gene: isolation and expression in developing thyroid, kidney and Wilms' tumors | journal = Development | volume = 116 | issue = 3 | pages = 611–23 | date = November 1992 | pmid = 1337742 | doi =  }}
| citations =
* {{cite journal | vauthors = Poleev A, Wendler F, Fickenscher H, Zannini MS, Yaginuma K, Abbott C, Plachov D | title = Distinct functional properties of three human paired-box-protein, PAX8, isoforms generated by alternative splicing in thyroid, kidney and Wilms' tumors | journal = European Journal of Biochemistry / FEBS | volume = 228 | issue = 3 | pages = 899–911 | date = March 1995 | pmid = 7737192 | doi = 10.1111/j.1432-1033.1995.tb20338.x }}
*{{cite journal | author=Poleev A, Fickenscher H, Mundlos S, ''et al.'' |title=PAX8, a human paired box gene: isolation and expression in developing thyroid, kidney and Wilms' tumors. |journal=Development |volume=116 |issue= 3 |pages= 611-23 |year= 1993 |pmid= 1337742 |doi=  }}
* {{cite journal | vauthors = Stapleton P, Weith A, Urbánek P, Kozmik Z, Busslinger M | title = Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9 | journal = Nature Genetics | volume = 3 | issue = 4 | pages = 292–8 | date = April 1993 | pmid = 7981748 | doi = 10.1038/ng0493-292 }}
*{{cite journal | author=Poleev A, Wendler F, Fickenscher H, ''et al.'' |title=Distinct functional properties of three human paired-box-protein, PAX8, isoforms generated by alternative splicing in thyroid, kidney and Wilms' tumors. |journal=Eur. J. Biochem. |volume=228 |issue= 3 |pages= 899-911 |year= 1995 |pmid= 7737192 |doi= }}
* {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | date = January 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
*{{cite journal | author=Stapleton P, Weith A, Urbánek P, ''et al.'' |title=Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9. |journal=Nat. Genet. |volume=3 |issue= 4 |pages= 292-8 |year= 1995 |pmid= 7981748 |doi= 10.1038/ng0493-292 }}
* {{cite journal | vauthors = Kozmik Z, Kurzbauer R, Dörfler P, Busslinger M | title = Alternative splicing of Pax-8 gene transcripts is developmentally regulated and generates isoforms with different transactivation properties | journal = Molecular and Cellular Biology | volume = 13 | issue = 10 | pages = 6024–35 | date = October 1993 | pmid = 8413205 | pmc = 364662 | doi = 10.1128/mcb.13.10.6024 }}
*{{cite journal | author=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1-2 |pages= 171-4 |year= 1994 |pmid= 8125298 |doi= }}
* {{cite journal | vauthors = Pilz AJ, Povey S, Gruss P, Abbott CM | title = Mapping of the human homologs of the murine paired-box-containing genes | journal = Mammalian Genome | volume = 4 | issue = 2 | pages = 78–82 | year = 1993 | pmid = 8431641 | doi = 10.1007/BF00290430 }}
*{{cite journal | author=Kozmik Z, Kurzbauer R, Dörfler P, Busslinger M |title=Alternative splicing of Pax-8 gene transcripts is developmentally regulated and generates isoforms with different transactivation properties. |journal=Mol. Cell. Biol. |volume=13 |issue= 10 |pages= 6024-35 |year= 1993 |pmid= 8413205 |doi= }}
* {{cite journal | vauthors = Bonaldo MF, Lennon G, Soares MB | title = Normalization and subtraction: two approaches to facilitate gene discovery | journal = Genome Research | volume = 6 | issue = 9 | pages = 791–806 | date = September 1996 | pmid = 8889548 | doi = 10.1101/gr.6.9.791 }}
*{{cite journal | author=Pilz AJ, Povey S, Gruss P, Abbott CM |title=Mapping of the human homologs of the murine paired-box-containing genes. |journal=Mamm. Genome |volume=4 |issue= 2 |pages= 78-82 |year= 1993 |pmid= 8431641 |doi= }}
* {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–56 | date = October 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
*{{cite journal | author=Bonaldo MF, Lennon G, Soares MB |title=Normalization and subtraction: two approaches to facilitate gene discovery. |journal=Genome Res. |volume=6 |issue= 9 |pages= 791-806 |year= 1997 |pmid= 8889548 |doi= }}
* {{cite journal | vauthors = Fraizer GC, Shimamura R, Zhang X, Saunders GF | title = PAX 8 regulates human WT1 transcription through a novel DNA binding site | journal = The Journal of Biological Chemistry | volume = 272 | issue = 49 | pages = 30678–87 | date = December 1997 | pmid = 9388203 | doi = 10.1074/jbc.272.49.30678 }}
*{{cite journal | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, ''et al.'' |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149-56 |year= 1997 |pmid= 9373149 |doi= }}
* {{cite journal | vauthors = Macchia PE, Lapi P, Krude H, Pirro MT, Missero C, Chiovato L, Souabni A, Baserga M, Tassi V, Pinchera A, Fenzi G, Grüters A, Busslinger M, Di Lauro R | title = PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis | journal = Nature Genetics | volume = 19 | issue = 1 | pages = 83–6 | date = May 1998 | pmid = 9590296 | doi = 10.1038/ng0598-83 }}
*{{cite journal | author=Fraizer GC, Shimamura R, Zhang X, Saunders GF |title=PAX 8 regulates human WT1 transcription through a novel DNA binding site. |journal=J. Biol. Chem. |volume=272 |issue= 49 |pages= 30678-87 |year= 1998 |pmid= 9388203 |doi= }}
* {{cite journal | vauthors = Mansouri A, Chowdhury K, Gruss P | title = Follicular cells of the thyroid gland require Pax8 gene function | journal = Nature Genetics | volume = 19 | issue = 1 | pages = 87–90 | date = May 1998 | pmid = 9590297 | doi = 10.1038/ng0598-87 }}
*{{cite journal | author=Macchia PE, Lapi P, Krude H, ''et al.'' |title=PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis. |journal=Nat. Genet. |volume=19 |issue= 1 |pages= 83-6 |year= 1998 |pmid= 9590296 |doi= 10.1038/ng0598-83 }}
* {{cite journal | vauthors = Tell G, Pellizzari L, Esposito G, Pucillo C, Macchia PE, Di Lauro R, Damante G | title = Structural defects of a Pax8 mutant that give rise to congenital hypothyroidism | journal = The Biochemical Journal | volume = 341 | issue = 1 | pages = 89–93 | date = July 1999 | pmid = 10377248 | pmc = 1220333 | doi = 10.1042/0264-6021:3410089 }}
*{{cite journal | author=Mansouri A, Chowdhury K, Gruss P |title=Follicular cells of the thyroid gland require Pax8 gene function. |journal=Nat. Genet. |volume=19 |issue= 1 |pages= 87-90 |year= 1998 |pmid= 9590297 |doi= 10.1038/ng0598-87 }}
* {{cite journal | vauthors = De Leo R, Miccadei S, Zammarchi E, Civitareale D | title = Role for p300 in Pax 8 induction of thyroperoxidase gene expression | journal = The Journal of Biological Chemistry | volume = 275 | issue = 44 | pages = 34100–5 | date = November 2000 | pmid = 10924503 | doi = 10.1074/jbc.M003043200 }}
*{{cite journal | author=Tell G, Pellizzari L, Esposito G, ''et al.'' |title=Structural defects of a Pax8 mutant that give rise to congenital hypothyroidism. |journal=Biochem. J. |volume=341 ( Pt 1) |issue= |pages= 89-93 |year= 1999 |pmid= 10377248 |doi= }}
* {{cite journal | vauthors = Roberts EC, Deed RW, Inoue T, Norton JD, Sharrocks AD | title = Id helix-loop-helix proteins antagonize pax transcription factor activity by inhibiting DNA binding | journal = Molecular and Cellular Biology | volume = 21 | issue = 2 | pages = 524–33 | date = January 2001 | pmid = 11134340 | pmc = 86614 | doi = 10.1128/MCB.21.2.524-533.2001 }}
*{{cite journal | author=De Leo R, Miccadei S, Zammarchi E, Civitareale D |title=Role for p300 in Pax 8 induction of thyroperoxidase gene expression. |journal=J. Biol. Chem. |volume=275 |issue= 44 |pages= 34100-5 |year= 2000 |pmid= 10924503 |doi= 10.1074/jbc.M003043200 }}
* {{cite journal | vauthors = Vilain C, Rydlewski C, Duprez L, Heinrichs C, Abramowicz M, Malvaux P, Renneboog B, Parma J, Costagliola S, Vassart G | title = Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8 | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 86 | issue = 1 | pages = 234–8 | date = January 2001 | pmid = 11232006 | doi = 10.1210/jc.86.1.234 }}
*{{cite journal | author=Roberts EC, Deed RW, Inoue T, ''et al.'' |title=Id helix-loop-helix proteins antagonize pax transcription factor activity by inhibiting DNA binding. |journal=Mol. Cell. Biol. |volume=21 |issue= 2 |pages= 524-33 |year= 2001 |pmid= 11134340 |doi= 10.1128/MCB.21.2.524-533.2001 }}
* {{cite journal | vauthors = Congdon T, Nguyen LQ, Nogueira CR, Habiby RL, Medeiros-Neto G, Kopp P | title = A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: evidence for phenotypic variability in mother and child | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 86 | issue = 8 | pages = 3962–7 | date = August 2001 | pmid = 11502839 | doi = 10.1210/jc.86.8.3962 }}
*{{cite journal | author=Vilain C, Rydlewski C, Duprez L, ''et al.'' |title=Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8. |journal=J. Clin. Endocrinol. Metab. |volume=86 |issue= 1 |pages= 234-8 |year= 2001 |pmid= 11232006 |doi= }}
* {{cite journal | vauthors = Miccadei S, De Leo R, Zammarchi E, Natali PG, Civitareale D | title = The synergistic activity of thyroid transcription factor 1 and Pax 8 relies on the promoter/enhancer interplay | journal = Molecular Endocrinology | volume = 16 | issue = 4 | pages = 837–46 | date = April 2002 | pmid = 11923479 | doi = 10.1210/me.16.4.837 }}
*{{cite journal | author=Congdon T, Nguyen LQ, Nogueira CR, ''et al.'' |title=A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: evidence for phenotypic variability in mother and child. |journal=J. Clin. Endocrinol. Metab. |volume=86 |issue= 8 |pages= 3962-7 |year= 2001 |pmid= 11502839 |doi= }}
* {{cite journal | vauthors = Marques AR, Espadinha C, Catarino AL, Moniz S, Pereira T, Sobrinho LG, Leite V | title = Expression of PAX8-PPAR gamma 1 rearrangements in both follicular thyroid carcinomas and adenomas | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 87 | issue = 8 | pages = 3947–52 | date = August 2002 | pmid = 12161538 | doi = 10.1210/jc.87.8.3947 }}
*{{cite journal | author=Miccadei S, De Leo R, Zammarchi E, ''et al.'' |title=The synergistic activity of thyroid transcription factor 1 and Pax 8 relies on the promoter/enhancer interplay. |journal=Mol. Endocrinol. |volume=16 |issue= 4 |pages= 837-46 |year= 2002 |pmid= 11923479 |doi= }}
* {{cite journal | vauthors = Di Palma T, Nitsch R, Mascia A, Nitsch L, Di Lauro R, Zannini M | title = The paired domain-containing factor Pax8 and the homeodomain-containing factor TTF-1 directly interact and synergistically activate transcription | journal = The Journal of Biological Chemistry | volume = 278 | issue = 5 | pages = 3395–402 | date = January 2003 | pmid = 12441357 | doi = 10.1074/jbc.M205977200 }}
*{{cite journal | author=Marques AR, Espadinha C, Catarino AL, ''et al.'' |title=Expression of PAX8-PPAR gamma 1 rearrangements in both follicular thyroid carcinomas and adenomas. |journal=J. Clin. Endocrinol. Metab. |volume=87 |issue= 8 |pages= 3947-52 |year= 2002 |pmid= 12161538 |doi= }}
*{{cite journal | author=Di Palma T, Nitsch R, Mascia A, ''et al.'' |title=The paired domain-containing factor Pax8 and the homeodomain-containing factor TTF-1 directly interact and synergistically activate transcription. |journal=J. Biol. Chem. |volume=278 |issue= 5 |pages= 3395-402 |year= 2003 |pmid= 12441357 |doi= 10.1074/jbc.M205977200 }}
*{{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 }}
}}
{{refend}}
{{refend}}


== External links ==
== External links ==
* {{MeshName|PAX8+protein,+human}}
* {{MeshName|PAX8+protein,+human}}
* {{cite web | url = http://xenbase.org/gene/showgene.do?method=displayGeneSummary&geneId=483692 | title = Xenbase Gene: Summary for pax8, species: Xenopus tropicalis | authorlink = | format = | work = [[Xenbase]]  | publisher = xenbase.org | pages = | archiveurl = | archivedate = | quote = A Xenopus laevis and tropicalis resource | accessdate = 2009-07-17}}


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{{Transcription factors}}
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[[Category:Transcription factors]]
[[Category:Transcription factors]]
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Latest revision as of 09:00, 28 September 2017

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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Paired box gene 8, also known as PAX8, is a protein which in humans is encoded by the PAX8 gene.[1]

Function

This gene is a member of the paired box (PAX) family of transcription factors. Members of this gene family typically encode proteins which contain a paired box domain, an octapeptide, and a paired-type homeodomain. The PAX gene family has an important role in the formation of tissues and organs during embryonic development and maintaining the normal function of some cells after birth. The PAX genes give instructions for making proteins that attach themselves to certain areas of DNA.[2] This nuclear protein is involved in thyroid follicular cell development and expression of thyroid-specific genes. PAX8 releases the hormones important for regulating growth, brain development, and metabolism. Also functions in very early stages of kidney organogenesis, the müllerian system, and the thymus.[3] Additionally, PAX8 is expressed in the renal excretory system, epithelial cells of the endocervix, endometrium, ovary, Fallopian tube, seminal vesicle, epididymis, pancreatic islet cells and lymphoid cells.[4] PAX8 and other transcription factors play a role in binding to DNA and regulating the genes that drive thyroid hormone synthesis (Tg, TPO, Slc5a5 and Tshr).

PAX8 (and PAX2) is one of the important regulators of urogenital system morphogenesis. They play a role in the specification of the first renal cells of the embryo and remain essential players throughout development.[5]

Clinical significance

Mutations in this gene have been associated with thyroid dysgenesis, thyroid follicular carcinomas and atypical follicular thyroid adenomas. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[1]

The PAX8 gene is also associated congenital hypothyroidism due to thyroid dysgenesis because of its role in growth and development of the thyroid gland. A mutation in the PAX8 gene could prevent or disrupt normal development. These mutations can affect different functions of the protein including DNA biding, gene activation, protein stability, and cooperation with the co-activator p300. PAX gene deficiencies can result in development defects called Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).

Cancer

PAX8 is considered a "master regulator transcription factor".[4] As a master regulator, it is possible that it regulates expression of genes other than thyroid-specific. Several known tumor suppressor genes like TP53 and WT1 have been identified as transcriptional targets in human astrocytoma cells. Over 90% of thyroid tumors arise from follicular thyroid cells.[4] A fusion protein, PAX8-PPAR-γ, is implicated in some follicular thyroid carcinomas and follicular-variant papillary thyroid carcinoma.[6] The mechanism for this transformation is not well understood, but there are several proposed possibilities.[7][8][9]

  • Inhibition of normal PPAR y function by chimeric PAX8/PPARy protein through a dominant negative effect
  • Activation of normal PPARy targets due to the over expression of the chimeric protein that contain all functional domains of wild-type PPAR y
  • Deregulation of PAX8 function
  • Activation of a set of genes unrelated to both wild-type PPARy and wild-type PAX8 pathways

The PAX 8 gene has some association with follicular thyroid tumors. PAX8/PPARy rearrangement account for 30-40% of conventional type follicular carcinomas[10] and less than 5% of oncocytic carcinomas (aka Hurthle-Cell Neoplasms).[11] Tumors expressing the PAX8/PPARy are usually present in at a young age, small in size, present in a solid/nested growth pattern and frequently involve vascular invasion. It has been observed that PAX8/PPAR y-positive tumors rarely express RAS mutations in combination. This suggests that follicular carcinomas develop in two distinct pathways either with PAX8/PPAR y or RAS.

Some whole-genome sequencing studies have shown that PAX8 also targets BRCA1 (carcinogenesis), MAPK pathways (thyroid malignancies), and Ccnb1 and Ccnb2 (cell-cycle processes). PAX8 is shown to be involved in tumor cell proliferation and differentiation, signal transduction, apoptosis, cell polarity and transport, cell motility and adhesion.[4]

Expression of PAX8 is increased in neoplastic renal tissues, Wilms tumors, ovarian cancer and Müllerian carcinomas. For this reason, the immunodetection of PAX8 is widely used for diagnosing primary and metastatic renal tumors. Re-activation of PAX8 (or Pax2) expression has been reported in pediatric Wilms Tumors, almost all subtypes of renal cell carcinoma, nephrogenic adenomas, ovarian cancer cells, bladder, prostate, and endometrial carcinomas.[5] The mechanism of switching on the genes is unknown. Some studies have suggested that the renal PAX genes act as pro-survival factors and allow tumor cells to resist apoptosis. Down regulation of the PAX gene expression inhibits cell growth and induces apoptosis. This could be a possible avenue for therapeutic targets in renal cancer.

Interactions

PAX8 has been shown to interact with NK2 homeobox 1.[12]

See also

References

  1. ↑ 1.0 1.1 "Entrez Gene: PAX8 paired box gene 8".
  2. ↑ "PAX8 gene". Genetics Home Reference. 2016-03-28. Retrieved 2016-04-05.
  3. ↑ Laury AR, Perets R, Piao H, Krane JF, Barletta JA, French C, Chirieac LR, Lis R, Loda M, Hornick JL, Drapkin R, Hirsch MS (June 2011). "A comprehensive analysis of PAX8 expression in human epithelial tumors". The American Journal of Surgical Pathology. 35 (6): 816–26. doi:10.1097/PAS.0b013e318216c112. PMID 21552115.
  4. ↑ 4.0 4.1 4.2 4.3 Fernández LP, López-Márquez A, Santisteban P (January 2015). "Thyroid transcription factors in development, differentiation and disease". Nature Reviews. Endocrinology. 11 (1): 29–42. doi:10.1038/nrendo.2014.186. PMID 25350068.
  5. ↑ 5.0 5.1 Sharma R, Sanchez-Ferras O, Bouchard M (August 2015). "Pax genes in renal development, disease and regeneration". Seminars in Cell & Developmental Biology. Paramutation & Pax Transcription Factors. 44: 97–106. doi:10.1016/j.semcdb.2015.09.016. PMID 26410163.
  6. ↑ Raman P, Koenig RJ (October 2014). "Pax-8-PPAR-γ fusion protein in thyroid carcinoma". Nature Reviews. Endocrinology. 10 (10): 616–23. doi:10.1038/nrendo.2014.115. PMC 4290886. PMID 25069464.
  7. ↑ Rüsch A, Erway LC, Oliver D, Vennström B, Forrest D (December 1998). "Thyroid hormone receptor beta-dependent expression of a potassium conductance in inner hair cells at the onset of hearing". Proceedings of the National Academy of Sciences of the United States of America. 95 (26): 15758–62. doi:10.1073/pnas.95.26.15758. PMC 28117. PMID 9861043.
  8. ↑ Weiss RE, Xu J, Ning G, Pohlenz J, O'Malley BW, Refetoff S (April 1999). "Mice deficient in the steroid receptor co-activator 1 (SRC-1) are resistant to thyroid hormone". The EMBO Journal. 18 (7): 1900–4. doi:10.1093/emboj/18.7.1900. PMC 1171275. PMID 10202153.
  9. ↑ Brown NS, Smart A, Sharma V, Brinkmeier ML, Greenlee L, Camper SA, Jensen DR, Eckel RH, Krezel W, Chambon P, Haugen BR (July 2000). "Thyroid hormone resistance and increased metabolic rate in the RXR-gamma-deficient mouse". The Journal of Clinical Investigation. 106 (1): 73–9. doi:10.1172/JCI9422. PMC 314362. PMID 10880050.
  10. ↑ Nikiforova MN, Lynch RA, Biddinger PW, Alexander EK, Dorn GW, Tallini G, Kroll TG, Nikiforov YE (May 2003). "RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma". The Journal of Clinical Endocrinology and Metabolism. 88 (5): 2318–26. doi:10.1210/jc.2002-021907. PMID 12727991.
  11. ↑ Abel ED, Boers ME, Pazos-Moura C, Moura E, Kaulbach H, Zakaria M, Lowell B, Radovick S, Liberman MC, Wondisford F (August 1999). "Divergent roles for thyroid hormone receptor beta isoforms in the endocrine axis and auditory system". The Journal of Clinical Investigation. 104 (3): 291–300. doi:10.1172/JCI6397. PMC 408418. PMID 10430610.
  12. ↑ Di Palma T, Nitsch R, Mascia A, Nitsch L, Di Lauro R, Zannini M (January 2003). "The paired domain-containing factor Pax8 and the homeodomain-containing factor TTF-1 directly interact and synergistically activate transcription". The Journal of Biological Chemistry. 278 (5): 3395–402. doi:10.1074/jbc.M205977200. PMID 12441357.

Further reading

  • Poleev A, Fickenscher H, Mundlos S, Winterpacht A, Zabel B, Fidler A, Gruss P, Plachov D (November 1992). "PAX8, a human paired box gene: isolation and expression in developing thyroid, kidney and Wilms' tumors". Development. 116 (3): 611–23. PMID 1337742.
  • Poleev A, Wendler F, Fickenscher H, Zannini MS, Yaginuma K, Abbott C, Plachov D (March 1995). "Distinct functional properties of three human paired-box-protein, PAX8, isoforms generated by alternative splicing in thyroid, kidney and Wilms' tumors". European Journal of Biochemistry / FEBS. 228 (3): 899–911. doi:10.1111/j.1432-1033.1995.tb20338.x. PMID 7737192.
  • Stapleton P, Weith A, Urbánek P, Kozmik Z, Busslinger M (April 1993). "Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9". Nature Genetics. 3 (4): 292–8. doi:10.1038/ng0493-292. PMID 7981748.
  • Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
  • Kozmik Z, Kurzbauer R, Dörfler P, Busslinger M (October 1993). "Alternative splicing of Pax-8 gene transcripts is developmentally regulated and generates isoforms with different transactivation properties". Molecular and Cellular Biology. 13 (10): 6024–35. doi:10.1128/mcb.13.10.6024. PMC 364662. PMID 8413205.
  • Pilz AJ, Povey S, Gruss P, Abbott CM (1993). "Mapping of the human homologs of the murine paired-box-containing genes". Mammalian Genome. 4 (2): 78–82. doi:10.1007/BF00290430. PMID 8431641.
  • Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
  • Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
  • Fraizer GC, Shimamura R, Zhang X, Saunders GF (December 1997). "PAX 8 regulates human WT1 transcription through a novel DNA binding site". The Journal of Biological Chemistry. 272 (49): 30678–87. doi:10.1074/jbc.272.49.30678. PMID 9388203.
  • Macchia PE, Lapi P, Krude H, Pirro MT, Missero C, Chiovato L, Souabni A, Baserga M, Tassi V, Pinchera A, Fenzi G, Grüters A, Busslinger M, Di Lauro R (May 1998). "PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis". Nature Genetics. 19 (1): 83–6. doi:10.1038/ng0598-83. PMID 9590296.
  • Mansouri A, Chowdhury K, Gruss P (May 1998). "Follicular cells of the thyroid gland require Pax8 gene function". Nature Genetics. 19 (1): 87–90. doi:10.1038/ng0598-87. PMID 9590297.
  • Tell G, Pellizzari L, Esposito G, Pucillo C, Macchia PE, Di Lauro R, Damante G (July 1999). "Structural defects of a Pax8 mutant that give rise to congenital hypothyroidism". The Biochemical Journal. 341 (1): 89–93. doi:10.1042/0264-6021:3410089. PMC 1220333. PMID 10377248.
  • De Leo R, Miccadei S, Zammarchi E, Civitareale D (November 2000). "Role for p300 in Pax 8 induction of thyroperoxidase gene expression". The Journal of Biological Chemistry. 275 (44): 34100–5. doi:10.1074/jbc.M003043200. PMID 10924503.
  • Roberts EC, Deed RW, Inoue T, Norton JD, Sharrocks AD (January 2001). "Id helix-loop-helix proteins antagonize pax transcription factor activity by inhibiting DNA binding". Molecular and Cellular Biology. 21 (2): 524–33. doi:10.1128/MCB.21.2.524-533.2001. PMC 86614. PMID 11134340.
  • Vilain C, Rydlewski C, Duprez L, Heinrichs C, Abramowicz M, Malvaux P, Renneboog B, Parma J, Costagliola S, Vassart G (January 2001). "Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8". The Journal of Clinical Endocrinology and Metabolism. 86 (1): 234–8. doi:10.1210/jc.86.1.234. PMID 11232006.
  • Congdon T, Nguyen LQ, Nogueira CR, Habiby RL, Medeiros-Neto G, Kopp P (August 2001). "A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: evidence for phenotypic variability in mother and child". The Journal of Clinical Endocrinology and Metabolism. 86 (8): 3962–7. doi:10.1210/jc.86.8.3962. PMID 11502839.
  • Miccadei S, De Leo R, Zammarchi E, Natali PG, Civitareale D (April 2002). "The synergistic activity of thyroid transcription factor 1 and Pax 8 relies on the promoter/enhancer interplay". Molecular Endocrinology. 16 (4): 837–46. doi:10.1210/me.16.4.837. PMID 11923479.
  • Marques AR, Espadinha C, Catarino AL, Moniz S, Pereira T, Sobrinho LG, Leite V (August 2002). "Expression of PAX8-PPAR gamma 1 rearrangements in both follicular thyroid carcinomas and adenomas". The Journal of Clinical Endocrinology and Metabolism. 87 (8): 3947–52. doi:10.1210/jc.87.8.3947. PMID 12161538.
  • Di Palma T, Nitsch R, Mascia A, Nitsch L, Di Lauro R, Zannini M (January 2003). "The paired domain-containing factor Pax8 and the homeodomain-containing factor TTF-1 directly interact and synergistically activate transcription". The Journal of Biological Chemistry. 278 (5): 3395–402. doi:10.1074/jbc.M205977200. PMID 12441357.

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.


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