Biology:PAX8

Short description: Mammalian protein found in humans

Generic protein structure example

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

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. 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. 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. 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.

PAX8 has been shown to interact with NK2 homeobox 1.

Clinical significance

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 binding, 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 mutations are associated with various forms of cancer.

Mechanisms

PAX8 is considered a "master regulator transcription factor". 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. A fusion protein, PAX8-PPAR-γ, is implicated in some follicular thyroid carcinomas and follicular-variant papillary thyroid carcinoma. The mechanism for this transformation is not well understood, but there are several proposed possibilities.

• 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. 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.

Alternate transcriptional splice variants, encoding different isoforms, have been characterized. 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.

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.

Associated cancer types

Mutations in this gene have been associated with thyroid dysgenesis, thyroid follicular carcinomas and atypical follicular thyroid adenomas.

PAX8/PPARy rearrangement account for 30-40% of conventional type follicular carcinomas., and less than 5% of oncocytic carcinomas (aka Hurthle-Cell Neoplasms).

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. Expression of PAX8 is also induced during the development of cervical cancer.

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.

See also

• Pax genes

Further reading

• "PAX8, a human paired box gene: isolation and expression in developing thyroid, kidney and Wilms' tumors". Development 116 (3): 611–23. November 1992. doi:10.1242/dev.116.3.611. PMID 1337742. 
• "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 228 (3): 899–911. March 1995. doi:10.1111/j.1432-1033.1995.tb20338.x. PMID 7737192. 
• "Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9". Nature Genetics 3 (4): 292–8. April 1993. doi:10.1038/ng0493-292. PMID 7981748. 
• "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–4. January 1994. doi:10.1016/0378-1119(94)90802-8. PMID 8125298. 
• "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. October 1993. doi:10.1128/mcb.13.10.6024. PMID 8413205. 
• "Mapping of the human homologs of the murine paired-box-containing genes". Mammalian Genome 4 (2): 78–82. 1993. doi:10.1007/BF00290430. PMID 8431641. 
• "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research 6 (9): 791–806. September 1996. doi:10.1101/gr.6.9.791. PMID 8889548. 
• "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. October 1997. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149. 
• "PAX 8 regulates human WT1 transcription through a novel DNA binding site". The Journal of Biological Chemistry 272 (49): 30678–87. December 1997. doi:10.1074/jbc.272.49.30678. PMID 9388203. 
• "PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis". Nature Genetics 19 (1): 83–6. May 1998. doi:10.1038/ng0598-83. PMID 9590296. 
• "Follicular cells of the thyroid gland require Pax8 gene function". Nature Genetics 19 (1): 87–90. May 1998. doi:10.1038/ng0598-87. PMID 9590297. 
• "Structural defects of a Pax8 mutant that give rise to congenital hypothyroidism". The Biochemical Journal 341 (1): 89–93. July 1999. doi:10.1042/0264-6021:3410089. PMID 10377248. 
• "Role for p300 in Pax 8 induction of thyroperoxidase gene expression". The Journal of Biological Chemistry 275 (44): 34100–5. November 2000. doi:10.1074/jbc.M003043200. PMID 10924503. 
• "Id helix-loop-helix proteins antagonize pax transcription factor activity by inhibiting DNA binding". Molecular and Cellular Biology 21 (2): 524–33. January 2001. doi:10.1128/MCB.21.2.524-533.2001. PMID 11134340. 
• "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. January 2001. doi:10.1210/jcem.86.1.7140. PMID 11232006. 
• "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. August 2001. doi:10.1210/jcem.86.8.7765. PMID 11502839. 
• "The synergistic activity of thyroid transcription factor 1 and Pax 8 relies on the promoter/enhancer interplay". Molecular Endocrinology 16 (4): 837–46. April 2002. doi:10.1210/me.16.4.837. PMID 11923479. 
• "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. August 2002. doi:10.1210/jcem.87.8.8756. PMID 12161538. 
• "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. January 2003. doi:10.1074/jbc.M205977200. PMID 12441357. 

External links

• PAX8+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
• "Xenbase Gene: Summary for pax8, species: Xenopus tropicalis". Xenbase. xenbase.org. http://xenbase.org/gene/showgene.do?method=displayGeneSummary&geneId=483692. "A Xenopus laevis and tropicalis resource" 

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