PAX8
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| Location (UCSC) | Chr 2: 113.22 – 113.28 Mb | Chr 2: 24.31 – 24.37 Mb | |||||||
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Paired box gene 8, also known as PAX8, is a protein which in humans is encoded by the PAX8 gene.[5]
Function
This gene is a member of the paired box (
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.[9]
PAX8 has been shown to
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".[8] 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.[8] A fusion protein, PAX8-PPAR-γ, is implicated in some follicular thyroid carcinomas and follicular-variant papillary thyroid carcinoma.[11] The mechanism for this transformation is not well understood, but there are several proposed possibilities.[12][13][14]
- 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.[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.
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.[8]
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.,[15] and less than 5% of oncocytic carcinomas (aka Hurthle-Cell Neoplasms).[16]
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.[9] Expression of PAX8 is also induced during the development of cervical cancer.[17]
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
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000125618 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026976 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b "Entrez Gene: PAX8 paired box gene 8".
- ^ "PAX8 gene". Genetics Home Reference. 2016-03-28. Retrieved 2016-04-05.
- S2CID 14297595.
- ^ S2CID 39778077.
- ^ PMID 26410163.
- PMID 12441357.
- PMID 25069464.
- PMID 9861043.
- PMID 10202153.
- PMID 10880050.
- PMID 12727991.
- PMID 10430610.
- PMID 33905146.
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. 228 (3): 899–911. 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. S2CID 21338655.
- 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. 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. 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. S2CID 30845070.
- Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. 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. 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. 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. S2CID 33957230.
- Mansouri A, Chowdhury K, Gruss P (May 1998). "Follicular cells of the thyroid gland require Pax8 gene function". Nature Genetics. 19 (1): 87–90. S2CID 205342136.
- 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. 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. 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. 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. 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. 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. 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. 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. PMID 12441357.
External links
- PAX8+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- "Xenbase Gene: Summary for pax8, species: Xenopus tropicalis". Xenbase. xenbase.org. Retrieved 2009-07-17.
A Xenopus laevis and tropicalis resource
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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