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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]


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).


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.


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

See also


  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.