Open Access Articles- Top Results for PITX2


SymbolsPITX2 ; ARP1; Brx1; IDG2; IGDS; IGDS2; IHG2; IRID2; Otlx2; PTX2; RGS; RIEG; RIEG1; RS
External IDsOMIM601542 MGI109340 HomoloGene55454 GeneCards: PITX2 Gene
RNA expression pattern
File:PBB GE PITX2 207558 s at tn.png
More reference expression data
RefSeq (mRNA)NM_000325NM_001042502
RefSeq (protein)NP_000316NP_001035967
Location (UCSC)Chr 4:
111.54 – 111.56 Mb
Chr 3:
129.2 – 129.22 Mb
PubMed search[1][2]

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]


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 deveopment.[10]

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,[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]


  1. ^ Arakawa H, Nakamura T, Zhadanov AB, Fidanza V, Yano T, Bullrich F et al. (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. PMC 22531. PMID 9539779. doi:10.1073/pnas.95.8.4573. 
  2. ^ Héon E, Sheth BP, Kalenak JW, Sunden SL, Streb LM, Taylor CM et al. (Aug 1995). "Linkage of autosomal dominant iris hypoplasia to the region of the Rieger syndrome locus (4q25)". Human Molecular Genetics 4 (8): 1435–9. PMID 7581385. doi:10.1093/hmg/4.8.1435. 
  3. ^ a b c "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. PMID 9708733. doi:10.1016/S0092-8674(00)81474-9. 
  5. ^ Campione M, Steinbeisser H, Schweickert A, Deissler K, van Bebber F, Lowe LA et al. (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. PMID 16835440. doi:10.1242/dev.02470. 
  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. PMC 3019256. PMID 21035439. doi:10.1016/j.ydbio.2010.10.028. 
  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. ^ 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. PMID 20978076. doi:10.1242/dev.053421. 
  10. ^ 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. PMID 21325833. doi:10.1159/000325218. 
  11. ^ 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. PMID 20372070. doi:10.4161/cc.9.7.11126. 
  12. ^ 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. PMID 22615897. doi:10.1371/journal.pone.0037076. 
  13. ^ Hirose H, Ishii H, Mimori K, Tanaka F, Takemasa I, Mizushima T et al. (Oct 2011). "The significance of PITX2 overexpression in human colorectal cancer". Annals of Surgical Oncology 18 (10): 3005–12. PMID 21479692. doi:10.1245/s10434-011-1653-z. 
  14. ^ Kioussi C, Briata P, Baek SH, Rose DW, Hamblet NS, Herman T et al. (Nov 2002). "Identification of a Wnt/Dvl/beta-Catenin --> Pitx2 pathway mediating cell-type-specific proliferation during development". Cell 111 (5): 673–85. PMID 12464179. doi:10.1016/s0092-8674(02)01084-x. 
  15. ^ a b Baek SH, Kioussi C, Briata P, Wang D, Nguyen HD, Ohgi KA et al. (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. PMID 12629224. doi:10.1073/pnas.0330217100. 
  16. ^ a b c d 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. Journal International Du Cancer 133 (3): 556–67. PMID 23354914. doi:10.1002/ijc.28060. 
  17. ^ a b c d Zhang JX, Tong ZT, Yang L, Wang F, Chai HP, Zhang F et al. (Jun 2013). "PITX2: a promising predictive biomarker of patients' prognosis and chemoradioresistance in esophageal squamous cell carcinoma". International Journal of Cancer. Journal International Du Cancer 132 (11): 2567–2577. PMID 23132660. doi:10.1002/ijc.27930. 

Further reading


External links

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