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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]
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.[9]
Pitx2 isoforms are expressed in a sexually dimorphic manner during rat gonadal development.[10]
Pitx2 is overexpressed in many cancers. For example, thyroid,[11] ovarian,[12] and colon cancer[13] 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,[14] cyclin D1,[15] and C-Myc.[15]
In renal cancer, Pitx2 regulates expression of ABCB1, a multidrug transporter, by binding to the promoter region of ABCB1.[16] Increased expression of Pitx2 in renal cancer cells is associated with increased expression of ABCB1.[16] Thus, renal cancer cells that overexpress ABCB1 have a greater resistance to chemotherapeutic agents.[16] 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.[16]
In human esophageal squamous cell carcinoma (ESCC), Pitx2 is overexpressed compared to normal esophageal squamous cells.[17] In addition, greater expression of Pitx2 is positively correlated with clinical aggressiveness of ESCC.[17] Also, ESCC patients with high Pitx2 expression did not respond as well to definitive chemoradiotherapy (CRT) compared to ESCC patients with low Pitx2 expression.[17] Thus, physicians may be able to use Pitx2 expression to predict how ESCC patients will respond to cancer treatment.[17]
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).[18][19][20] 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).[18] 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.[19] 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.[20]
↑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. PMID7581385.
↑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. PMID9708733.
↑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. PMID10021341.
↑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. PMID16835440.
↑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. PMID10662647.
↑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. PMID20978076.
↑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. PMID21325833.
↑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. PMID20372070.
↑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. PMID21479692.
↑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. PMID12464179.
↑ 16.016.116.216.3Lee 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. PMID23354914.
↑ 17.017.117.217.3Zhang 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. PMID23132660.
↑ 20.020.1Dong, 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. PMID12732450.
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. PMID16274491.
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. PMID1303248.
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. PMID8942889.
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. PMID8944018.
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. PMID9437321.
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. PMID9618168.
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. PMID9685346.
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. PMID9708732.
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. PMID10372733.
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. PMID11487566.
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. PMID11763998.
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. PMID11821690.
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. PMID11948188.
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. PMID12130547.