PITX2
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| Location (UCSC) | Chr 4: 110.62 – 110.64 Mb | Chr 3: 128.99 – 129.01 Mb | |||||||
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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.[5][6][7]
Function
This gene encodes a member of the RIEG/PITX homeobox family, which is in the
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
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.[13] 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.[14]
Pitx2 plays a role in limb
Pitx2 isoforms are expressed in a sexually dimorphic manner during rat gonadal development.[16]
Pitx2 expression has been shown to be important for normal anterior pituitary gland development. Studies using mice embryos established Pitx2 expression is required in a dosage dependent manner. Mice with a homozygous null mutation of the Pitx2 gene showed that it is not required for initial pituitary formation but is needed for further development. Littermates of normal homozygotes, Pitx2+/+, versus homozygous null, Pitx2-/-, at embryonic day 10.5 provided a comparison of differing pouch sizes and cell types. Mice with the homozygous null gene had a smaller pouch and mesenchymal cell growth and differentiation arrested. While embryos with a hypomorphic mutation, Pitx2neo/+, of the gene were considered morphologically normal.[17] Along with normal pituitary expansion, Pitx2 is needed for normal expression of cell transcription genes of hormones produced in the anterior pituitary. Of which are luteinizing hormone (LH), follicle stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH), growth hormone (GH), and thyroid stimulating hormone (TSH). A study conducted using Pitx2neo/neo mice at postnatal day 1, found the transcripts of hormone genes for LH beta (LHb) and FSH beta (FSHb), and GnRH receptor (GnRHR) were nearly absent or nearly abolished, respectively. While transcription genes for GH and TSH producing cells, and growth hormone releasing hormone receptor (GHRHR) of Pitx2neo homozygous mice were moderately reduced. Further analysis of the transcription factors, Gata2, Egr1 and SF1, involved in LHb and FSHb differentiation found a reduction or absence of them in Pitx2neo/neo mice. The transcription factors, Prop1 and Pit1, which control development of GH and TSH producing cells, were also studied in Pitx2neo homozygous mice but only Pit1 expression was reduced. A reduction or absence of the transcription factors of the gonadotropin cells of the anterior pituitary leads to a loss of full pituitary cell function. [18]
Clinical significance
Mutations in this gene are associated with
Pitx2 is overexpressed in many cancers. For example, thyroid,[19] ovarian,[20] and colon cancer[21] 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,[22] cyclin D1,[23] and C-Myc.[23]
In
In human esophageal
In
Studies have also shown that Pitx2 displays an oncogenic role that is correlated with patients that have lung adenocarcinoma (LUAD). Pitx2 was overexpressed in LUAD when compared with neighboring normal tissues and is reported to increase clinical stages of the carcinoma and decrease survival. Patients with LUAD that presented with higher levels of Pitx2 had a lower overall survival rate compared to those with lower levels of Pitx2. The Pitx2 gene plays a role in lung adenocarcinoma that is dependent on activating the Wnt/β-catenin signaling pathway. When analyzing experimental findings from this Wnt/β-catenin signaling pathway, a TCGA dataset showed that Pitx2 had a positive correlation with WNT3A. These results propose that Pixt2 is directly bound to the WNT3A promoter region which will enhance WNT3A's transcription. This transcriptional regulation of WNT3A has been reported to encourage migration and the infiltration process of LUAD which can worsen a LUAD patients’ prognosis. Experimental knockdown of Pixt2 repressed tumor growth of LUAD; this supports the claim that Pixt2 is associated with the tumorigenesis of cancers, specifically in lung adenocarcinoma. These results suggest that Pitx2 may have a potential to serve as a biomarker for patients that present with LUAD.
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000164093 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028023 – 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.
- PMID 9539779.
- PMID 7581385.
- ^ a b c "Entrez Gene: PITX2 paired-like homeodomain transcription factor 2".
- S2CID 14375165.
- PMID 10021341.
- PMID 16835440.
- PMID 21035439.
- PMID 10662647.
- S2CID 40022353.
- PMID 25496870.
- PMID 20978076.
- PMID 21325833.
- PMID 10498698.
- PMID 11807026.
- PMID 20372070.
- PMID 22615897.
- S2CID 25710972.
- S2CID 16108479.
- ^ PMID 12629224.
- ^ S2CID 39427967.
- ^ S2CID 44870191.
- ^ PMID 26657035.
- ^ PMID 25893250.
- ^ PMID 24604414.
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. PMID 12732450.
- Hjalt TA, Semina EV (Nov 2005). "Current molecular understanding of Axenfeld-Rieger syndrome". Expert Reviews in Molecular Medicine. 7 (25): 1–17. S2CID 37108996.
- 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. S2CID 8778187.
- 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. 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. S2CID 21122544.
- 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. 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. 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. 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. S2CID 17712261.
- 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. 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. 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. 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. 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. 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. S2CID 26094053.
- 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. 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. PMID 12130547.
External links
- PITX2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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