PITX2

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Paired-like homeodomain transcription factor 2 also known as pituitary homeobox 2 is a protein that in humans is encoded by the PITX2 gene.[1][2][3]

Function

This gene encodes a member of the RIEG/PITX homeobox family, which is in the bicoid class of homeodomain proteins. This protein acts as a transcription factor[4] and regulates procollagen lysyl hydroxylase gene expression. This protein is involved in the development of the eye, tooth and abdominal organs. This protein acts as a transcriptional regulator involved in basal and hormone-regulated activity of prolactin. A similar protein in other vertebrates is involved in the determination of left-right asymmetry during development. Three transcript variants encoding distinct isoforms have been identified for this gene.[3]

Pitx2 is responsible for the establishment of the left-right axis, the asymmetrical development of the heart, lungs, and spleen, twisting of the gut and stomach, as well as the development of the eyes. Once activated Pitx2 will be locally expressed in the left lateral mesoderm, tubular heart, and early gut which leads to the asymmetrical development of organs and looping of the gut. When Pitx2 is deleted, the irregular morphogenesis of organs results on the left hand side. Pitx2 is left-laterally expressed controlling the morphology of the left visceral organs. Expression of Pitx2 is controlled by an intronic enhancer ASE and Nodal. It appears that while Nodal controls cranial expression of Pitx2, ASE controls left – right expression of Pitx2, which leads to the asymmetrical development of the left sided visceral organs, such as the spleen and liver. Collectively, Pitx2 first acts to prevent the apoptosis of the extraocular muscles followed by acting as the myogenic programmer of the extraocular muscle cells.[5][6][7] There have also been studies showing different isoforms of the transcription factor: Pitx2a, Pitx2b, and Pitx2c, each with distinct and non-overlapping functions.[8]

Studies have shown that in chick embryos , Pitx2 is a direct regulator of cVg1, a growth factor homologous to mammalian GDF1. cVg1 is a Transforming growth factor beta signal that is expressed posteriorly before the formation of the embryo germ layers.[9] The Pitx2 regulation of cVg1 is essential both during normal embryonic development and during establishment of polarity in twins created by experimental division of a single, original embryo. Pitx2 is shown to be essential for upregulation of cVg1 through the binding of enhancers, and is necessary for the proper expression of cVg1 in the posterior marginal zone. Expression of cVg1 in the PMZ is in turn necessary for the proper development of the primitive streak. Experimental knockouts of the PITX2 gene are associated with the subsequent upregulation of related Pitx1, which is able to partially compensate for the loss of Pitx2. Pitx2's ability to regulate the polarity of the embryo may be responsible for the ability of developing chicks to establish proper polarity in embryos created by cuts performed as late as the blastoderm stage.[10]

Pitx2 plays a role in limb myogenesis. Pitx2 can determine the development and activation of the MyoD gene (the gene responsible for skeletal myogenesis). Studies have shown that expression of Pitx2 happens before MyoD is expressed in muscles. Further studies show that Pitx2 is directly recruited to act on the MyoD core enhancer and thus, directing the expression of the MyoD gene. Pitx 2 is in a parallel pathway with Myf5 and Myf6, as both paths effect expression of MyoD. However, in the absence of the parallel pathway, Pitx2 can continue activating MyoD genes. The expression of Pitx2 saves MyoD gene expression and keeps expressing this gene for limb myogenesis. Yet, the Pitx 2 pathway is PAX3 dependent and requires this gene to enact limb myogenesis. Studies support this finding as in the absence of PAX3, there is Pitx2 expression deficit and thus, MyoD does not express itself in limb myogenesis. The Pitx2 gene is thus shown to be downstream of Pax3 and serve as an intermediate between Pax3 and MyoD. In conclusion, Pitx2 plays an integral role in limb myogenesis.[11]

Pitx2 isoforms are expressed in a sexually dimorphic manner during rat gonadal development.[12]

Clinical significance

Mutations in this gene are associated with Axenfeld-Rieger syndrome (ARS), iridogoniodysgenesis syndrome (IGDS), and sporadic cases of Peters anomaly. This protein plays a role in the terminal differentiation of somatotroph and lactotroph cell phenotypes.[3]

Pitx2 is overexpressed in many cancers. For example, thyroid,[13] ovarian,[14] and colon cancer[15] all have higher levels of Pitx2 compared to noncancerous tissues. Scientists speculate that cancer cells improperly turn on Pitx2, leading to uncontrolled cell proliferation. This is consistent with the role of Pitx2 in regulating the growth-regulating genes cyclin D2,[16] cyclin D1,[17] and C-Myc.[17]

In renal cancer, Pitx2 regulates expression of ABCB1, a multidrug transporter, by binding to the promoter region of ABCB1.[18] Increased expression of Pitx2 in renal cancer cells is associated with increased expression of ABCB1.[18] Thus, renal cancer cells that overexpress ABCB1 have a greater resistance to chemotherapeutic agents.[18] In experiments where Pitx2 expression was decreased, renal cancer cells had decreased cell proliferation and greater susceptibility to doxorubicin treatment, which is consistent with other results.[18]

In human esophageal squamous cell carcinoma (ESCC), Pitx2 is overexpressed compared to normal esophageal squamous cells.[19] In addition, greater expression of Pitx2 is positively correlated with clinical aggressiveness of ESCC.[19] Also, ESCC patients with high Pitx2 expression did not respond as well to definitive chemoradiotherapy (CRT) compared to ESCC patients with low Pitx2 expression.[19] Thus, physicians may be able to use Pitx2 expression to predict how ESCC patients will respond to cancer treatment.[19]

In Congenital Heart Disease, heterozygous mutations in Pitx2 have been involved in the development of Tetralogy of Fallot, ventricular septal defects, atrial septal defects, transposition of great arteries, and endocardial cushion defect (ECD).[20][21][22] The mutations of the Pitx2 gene are created through alternative splicing. The isoform of Pitx2 important for cardiogenesis is Pitx2c. The lack of expression of this particular isoform correlates with these congenital defects. Pitx2 mutations significantly reduce transcriptional activity of Pitx2 and synergistic activation between Pitx2 and NKX2(also important for development of the heart).[20] The large phenotypic spectrum due to the mutation of Pitx2 may be attributed to a variety of factors including: different genetic backgrounds, epigenetic modifiers and delayed/complete penetrance.[21] It is important to note that the mutation of Pitx2 is not defined as the cause of these congenital heart defects, but currently perceived as a risk factor for their development.[22]

References

  1. ↑ Arakawa H, Nakamura T, Zhadanov AB, Fidanza V, Yano T, Bullrich F, Shimizu M, Blechman J, Mazo A, Canaani E, Croce CM (Apr 1998). "Identification and characterization of the ARP1 gene, a target for the human acute leukemia ALL1 gene". Proceedings of the National Academy of Sciences of the United States of America. 95 (8): 4573–8. doi:10.1073/pnas.95.8.4573. PMC 22531. PMID 9539779.
  2. ↑ Héon E, Sheth BP, Kalenak JW, Sunden SL, Streb LM, Taylor CM, Alward WL, Sheffield VC, Stone EM (Aug 1995). "Linkage of autosomal dominant iris hypoplasia to the region of the Rieger syndrome locus (4q25)". Human Molecular Genetics. 4 (8): 1435–9. doi:10.1093/hmg/4.8.1435. PMID 7581385.
  3. ↑ 3.0 3.1 3.2 "Entrez Gene: PITX2 paired-like homeodomain transcription factor 2".
  4. ↑ Logan M, Pagán-Westphal SM, Smith DM, Paganessi L, Tabin CJ (Aug 1998). "The transcription factor Pitx2 mediates situs-specific morphogenesis in response to left-right asymmetric signals". Cell. 94 (3): 307–17. doi:10.1016/S0092-8674(00)81474-9. PMID 9708733.
  5. ↑ Campione M, Steinbeisser H, Schweickert A, Deissler K, van Bebber F, Lowe LA, Nowotschin S, Viebahn C, Haffter P, Kuehn MR, Blum M (Mar 1999). "The homeobox gene Pitx2: mediator of asymmetric left-right signaling in vertebrate heart and gut looping". Development. 126 (6): 1225–34. PMID 10021341.
  6. ↑ Shiratori H, Yashiro K, Shen MM, Hamada H (Aug 2006). "Conserved regulation and role of Pitx2 in situs-specific morphogenesis of visceral organs". Development. 133 (15): 3015–25. doi:10.1242/dev.02470. PMID 16835440.
  7. ↑ Zacharias AL, Lewandoski M, Rudnicki MA, Gage PJ (Jan 2011). "Pitx2 is an upstream activator of extraocular myogenesis and survival". Developmental Biology. 349 (2): 395–405. doi:10.1016/j.ydbio.2010.10.028. PMC 3019256. PMID 21035439.
  8. ↑ Essner JJ, Branford WW, Zhang J, Yost HJ (Mar 2000). "Mesendoderm and left-right brain, heart and gut development are differentially regulated by pitx2 isoforms". Development. 127 (5): 1081–93. PMID 10662647.
  9. ↑ Weeks, D.L.; Melton, D.A. (December 1987). "A maternal mRNA localized to the vegetal hemisphere in xenopus eggs codes for a growth factor related to TGF-β". Cell. 51 (5): 861–867. doi:10.1016/0092-8674(87)90109-7.
  10. ↑ Torlopp A, Khan MA, Oliveira NM, Lekk I, Soto-Jimenez LM, Sosinsky A, Stern C (Dec 2014). "The transcription factor Pitx2 positions the embryonic axis and regulates twinning". eLife. 3: e03743. doi:10.7554/eLife.03743. PMID 25496870.
  11. ↑ L'honoré A, Ouimette JF, Lavertu-Jolin M, Drouin J (Nov 2010). "Pitx2 defines alternate pathways acting through MyoD during limb and somitic myogenesis". Development. 137 (22): 3847–56. doi:10.1242/dev.053421. PMID 20978076.
  12. ↑ Nandi SS, Ghosh P, Roy SS (2011). "Expression of PITX2 homeodomain transcription factor during rat gonadal development in a sexually dimorphic manner". Cellular Physiology and Biochemistry. 27 (2): 159–70. doi:10.1159/000325218. PMID 21325833.
  13. ↑ Huang Y, Guigon CJ, Fan J, Cheng SY, Zhu GZ (Apr 2010). "Pituitary homeobox 2 (PITX2) promotes thyroid carcinogenesis by activation of cyclin D2". Cell Cycle. 9 (7): 1333–41. doi:10.4161/cc.9.7.11126. PMID 20372070.
  14. ↑ Fung FK, Chan DW, Liu VW, Leung TH, Cheung AN, Ngan HY (2012). "Increased expression of PITX2 transcription factor contributes to ovarian cancer progression". PLOS ONE. 7 (5): e37076. doi:10.1371/journal.pone.0037076. PMC 3352869. PMID 22615897.
  15. ↑ Hirose H, Ishii H, Mimori K, Tanaka F, Takemasa I, Mizushima T, Ikeda M, Yamamoto H, Sekimoto M, Doki Y, Mori M (Oct 2011). "The significance of PITX2 overexpression in human colorectal cancer". Annals of Surgical Oncology. 18 (10): 3005–12. doi:10.1245/s10434-011-1653-z. PMID 21479692.
  16. ↑ Kioussi C, Briata P, Baek SH, Rose DW, Hamblet NS, Herman T, Ohgi KA, Lin C, Gleiberman A, Wang J, Brault V, Ruiz-Lozano P, Nguyen HD, Kemler R, Glass CK, Wynshaw-Boris A, Rosenfeld MG (Nov 2002). "Identification of a Wnt/Dvl/beta-Catenin --> Pitx2 pathway mediating cell-type-specific proliferation during development". Cell. 111 (5): 673–85. doi:10.1016/s0092-8674(02)01084-x. PMID 12464179.
  17. ↑ 17.0 17.1 Baek SH, Kioussi C, Briata P, Wang D, Nguyen HD, Ohgi KA, Glass CK, Wynshaw-Boris A, Rose DW, Rosenfeld MG (Mar 2003). "Regulated subset of G1 growth-control genes in response to derepression by the Wnt pathway". Proceedings of the National Academy of Sciences of the United States of America. 100 (6): 3245–3250. doi:10.1073/pnas.0330217100. PMC 152277. PMID 12629224.
  18. ↑ 18.0 18.1 18.2 18.3 Lee WK, Chakraborty PK, Thévenod F (Aug 2013). "Pituitary homeobox 2 (PITX2) protects renal cancer cell lines against doxorubicin toxicity by transcriptional activation of the multidrug transporter ABCB1". International Journal of Cancer. 133 (3): 556–67. doi:10.1002/ijc.28060. PMID 23354914.
  19. ↑ 19.0 19.1 19.2 19.3 Zhang JX, Tong ZT, Yang L, Wang F, Chai HP, Zhang F, Xie MR, Zhang AL, Wu LM, Hong H, Yin L, Wang H, Wang HY, Zhao Y (Jun 2013). "PITX2: a promising predictive biomarker of patients' prognosis and chemoradioresistance in esophageal squamous cell carcinoma". International Journal of Cancer. 132 (11): 2567–2577. doi:10.1002/ijc.27930. PMID 23132660.
  20. ↑ 20.0 20.1 Sun, Y (February 15, 2016). "PITX2 loss-of-function mutation contributes to tetralogy of Fallot". Gene. 577: 258–264. doi:10.1016/j.gene.2015.12.001. PMID 26657035.
  21. ↑ 21.0 21.1 Zhao, C (April 20, 2015). "PITX2 Loss-of-Function Mutation contributes to Congenital Endocardial Cushion Defect and Axenfold-Rieger Syndrome". PLOS ONE. 10: e0124409. doi:10.1371/journal.pone.0124409. PMC 4404345. PMID 25893250.
  22. ↑ 22.0 22.1 Dong, Wei (January 14, 2014). "Novel Pitx2c loss-of-function mutations associated with complex congenital heart disease". International Journal of Molecular Medicine. doi:10.3892/ijmm.2014.168.

Further reading

  • Franco D, Campione M (May 2003). "The role of Pitx2 during cardiac development. Linking left-right signaling and congenital heart diseases". Trends in Cardiovascular Medicine. 13 (4): 157–63. doi:10.1016/S1050-1738(03)00039-2. PMID 12732450.
  • Hjalt TA, Semina EV (Nov 2005). "Current molecular understanding of Axenfeld-Rieger syndrome". Expert Reviews in Molecular Medicine. 7 (25): 1–17. doi:10.1017/S1462399405010082. PMID 16274491.
  • Murray JC, Bennett SR, Kwitek AE, Small KW, Schinzel A, Alward WL, Weber JL, Bell GI, Buetow KH (Sep 1992). "Linkage of Rieger syndrome to the region of the epidermal growth factor gene on chromosome 4". Nature Genetics. 2 (1): 46–9. doi:10.1038/ng0992-46. PMID 1303248.
  • Walter MA, Mirzayans F, Mears AJ, Hickey K, Pearce WG (Nov 1996). "Autosomal-dominant iridogoniodysgenesis and Axenfeld-Rieger syndrome are genetically distinct". Ophthalmology. 103 (11): 1907–15. doi:10.1016/s0161-6420(96)30408-9. PMID 8942889.
  • Semina EV, Reiter R, Leysens NJ, Alward WL, Small KW, Datson NA, Siegel-Bartelt J, Bierke-Nelson D, Bitoun P, Zabel BU, Carey JC, Murray JC (Dec 1996). "Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome". Nature Genetics. 14 (4): 392–9. doi:10.1038/ng1296-392. PMID 8944018.
  • Alward WL, Semina EV, Kalenak JW, Héon E, Sheth BP, Stone EM, Murray JC (Jan 1998). "Autosomal dominant iris hypoplasia is caused by a mutation in the Rieger syndrome (RIEG/PITX2) gene". American Journal of Ophthalmology. 125 (1): 98–100. doi:10.1016/S0002-9394(99)80242-6. PMID 9437321.
  • Kulak SC, Kozlowski K, Semina EV, Pearce WG, Walter MA (Jul 1998). "Mutation in the RIEG1 gene in patients with iridogoniodysgenesis syndrome". Human Molecular Genetics. 7 (7): 1113–7. doi:10.1093/hmg/7.7.1113. PMID 9618168.
  • Amendt BA, Sutherland LB, Semina EV, Russo AF (Aug 1998). "The molecular basis of Rieger syndrome. Analysis of Pitx2 homeodomain protein activities". The Journal of Biological Chemistry. 273 (32): 20066–72. doi:10.1074/jbc.273.32.20066. PMID 9685346.
  • Yoshioka H, Meno C, Koshiba K, Sugihara M, Itoh H, Ishimaru Y, Inoue T, Ohuchi H, Semina EV, Murray JC, Hamada H, Noji S (Aug 1998). "Pitx2, a bicoid-type homeobox gene, is involved in a lefty-signaling pathway in determination of left-right asymmetry". Cell. 94 (3): 299–305. doi:10.1016/S0092-8674(00)81473-7. PMID 9708732.
  • Doward W, Perveen R, Lloyd IC, Ridgway AE, Wilson L, Black GC (Feb 1999). "A mutation in the RIEG1 gene associated with Peters' anomaly". Journal of Medical Genetics. 36 (2): 152–5. doi:10.1136/jmg.36.2.152. PMC 1734311. PMID 10051017.
  • Pellegrini-Bouiller I, Manrique C, Gunz G, Grino M, Zamora AJ, Figarella-Branger D, Grisoli F, Jaquet P, Enjalbert A (Jun 1999). "Expression of the members of the Ptx family of transcription factors in human pituitary adenomas". The Journal of Clinical Endocrinology and Metabolism. 84 (6): 2212–20. doi:10.1210/jc.84.6.2212. PMID 10372733.
  • Hjalt TA, Amendt BA, Murray JC (Feb 2001). "PITX2 regulates procollagen lysyl hydroxylase (PLOD) gene expression: implications for the pathology of Rieger syndrome". The Journal of Cell Biology. 152 (3): 545–52. doi:10.1083/jcb.152.3.545. PMC 2196000. PMID 11157981.
  • Priston M, Kozlowski K, Gill D, Letwin K, Buys Y, Levin AV, Walter MA, Héon E (Aug 2001). "Functional analyses of two newly identified PITX2 mutants reveal a novel molecular mechanism for Axenfeld-Rieger syndrome". Human Molecular Genetics. 10 (16): 1631–8. doi:10.1093/hmg/10.16.1631. PMID 11487566.
  • Green PD, Hjalt TA, Kirk DE, Sutherland LB, Thomas BL, Sharpe PT, Snead ML, Murray JC, Russo AF, Amendt BA (2002). "Antagonistic regulation of Dlx2 expression by PITX2 and Msx2: implications for tooth development". Gene Expression. 9 (6): 265–81. PMID 11763998.
  • Vincent AL, Billingsley G, Buys Y, Levin AV, Priston M, Trope G, Williams-Lyn D, Héon E (Feb 2002). "Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene". American Journal of Human Genetics. 70 (2): 448–60. doi:10.1086/338709. PMC 384919. PMID 11774072.
  • Borges AS, Susanna R, Carani JC, Betinjane AJ, Alward WL, Stone EM, Sheffield VC, Nishimura DY (Feb 2002). "Genetic analysis of PITX2 and FOXC1 in Rieger Syndrome patients from Brazil". Journal of Glaucoma. 11 (1): 51–6. doi:10.1097/00061198-200202000-00010. PMID 11821690.
  • Cox CJ, Espinoza HM, McWilliams B, Chappell K, Morton L, Hjalt TA, Semina EV, Amendt BA (Jul 2002). "Differential regulation of gene expression by PITX2 isoforms". The Journal of Biological Chemistry. 277 (28): 25001–10. doi:10.1074/jbc.M201737200. PMID 11948188.
  • Quentien MH, Pitoia F, Gunz G, Guillet MP, Enjalbert A, Pellegrini I (Aug 2002). "Regulation of prolactin, GH, and Pit-1 gene expression in anterior pituitary by Pitx2: An approach using Pitx2 mutants". Endocrinology. 143 (8): 2839–51. doi:10.1210/en.143.8.2839. PMID 12130547.

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