PITX2

PITX2
已知的結構
PDB	直系同源搜索: PDBe RCSB
PDBID列表
	2L7F、2L7M、2LKX
識別號
別名	PITX2；, ARP1, Brx1, IDG2, IGDS, IGDS2, IHG2, IRID2, Otlx2, PTX2, RGS, RIEG, RIEG1, RS, paired like homeodomain 2, ASGD4
外部ID	OMIM：601542 MGI：109340 HomoloGene：55454 GeneCards：PITX2
相關疾病
	Axenfeld-Rieger syndrome type 1、虹膜發育不良綜合徵、ring dermoid of cornea、Rieger anomaly
基因位置（人類）
染色體	4號染色體
終止	110,642,123 bp
基因位置（小鼠）
染色體	小鼠3號染色體
終止	129,013,240 bp
RNA表達模式
	查閱更多表達數據
基因本體
分子功能	• 相同蛋白質結合; • protein homodimerization activity; • transcription cis-regulatory region binding; • sequence-specific DNA binding; • DNA結合; • 轉錄共激活因子活性; • chromatin DNA binding; • DNA-binding transcription activator activity, RNA polymerase II-specific; • 血漿蛋白結合; • RNA polymerase II cis-regulatory region sequence-specific DNA binding; • chromatin binding; • ribonucleoprotein complex binding; • DNA結合轉錄因子活性; • DNA結合轉錄阻遏物活性，RNA聚合酶II特異性; • 轉錄因子結合; • 磷蛋白結合; • DNA-binding transcription factor activity, RNA polymerase II-specific;
細胞組分	• 細胞核; • 細胞質; • 轉錄調節複合物; • 核質;
生物學過程	• response to vitamin A; • female gonad development; • vascular associated smooth muscle cell differentiation; • regulation of transcription by RNA polymerase II; • skeletal muscle tissue development; • cell proliferation involved in outflow tract morphogenesis; • prolactin secreting cell differentiation; • in utero embryonic development; • 垂體的發生; • 血管發生; • regulation of cell population proliferation; • myoblast fusion; • hair cell differentiation; • 脾的發生; • regulation of transcription, DNA-templated; • transcription by RNA polymerase II; • embryonic camera-type eye development; • ventricular septum morphogenesis; • endodermal digestive tract morphogenesis; • determination of left/right symmetry; • cardiac muscle tissue development; • positive regulation of transcription, DNA-templated; • subthalamic nucleus development; • ventricular cardiac muscle cell development; • left/right axis specification; • hypothalamus cell migration; • animal organ morphogenesis; • regulation of cell migration; • 心臟發育; • embryonic digestive tract morphogenesis; • branching involved in blood vessel morphogenesis; • cardiac muscle cell differentiation; • digestive system development; • multicellular organism development; • atrioventricular valve development; • pulmonary vein morphogenesis; • cardiac neural crest cell migration involved in outflow tract morphogenesis; • embryonic hindlimb morphogenesis; • lung development; • superior vena cava morphogenesis; • positive regulation of DNA binding; • extraocular skeletal muscle development; • pulmonary myocardium development; • deltoid tuberosity development; • atrial cardiac muscle tissue morphogenesis; • male gonad development; • anatomical structure morphogenesis; • brain development; • neuron differentiation; • odontogenesis of dentin-containing tooth; • Wnt信號通路; • left lung morphogenesis; • somatotropin secreting cell differentiation; • positive regulation of myoblast proliferation; • camera-type eye development; • response to hormone; • odontogenesis; • iris morphogenesis; • neuron migration; • negative regulation of transcription by RNA polymerase II; • positive regulation of transcription by RNA polymerase II;
	Sources:Amigo / QuickGO
直系同源
	5308
	18741
	ENSG00000164093
	ENSMUSG00000028023
	Q99697
	P97474
NM_000325; NM_001204397; NM_001204398; NM_001204399; NM_153426;
	NM_153427
	NM_001042502; NM_001042504; NM_001286942; NM_001287048; NM_011098
NP_000316; NP_001191326; NP_001191327; NP_001191328; NP_700475;
	NP_700476
	NP_001035967; NP_001035969; NP_001273871; NP_001273977; NP_035228
	維基數據
檢視/編輯人類	檢視/編輯小鼠

PITX2（Paired-like homeodomain transcription factor 2（類成對同源框轉錄因子2）/pituitary homeobox 2（垂體同源框2））是一個位於人第四號染色體上的基因，由其編碼的蛋白為PITX2^[6]^[7]^[8]。

功能

PITX2蛋白屬於RIEG/PITX同源框蛋白家族，有一個屬於Bicoid（英語：Bicoid）蛋白家族的同源結構域。從功能上說，PITX2是一種轉錄因子^[9]，主要調控前膠原賴氨酰羥化酶（英語：lysyl hydroxylase）（procollagen lysyl hydroxylase）基因的表達。賴氨酰羥化酶參與眼、牙，以及腹部器官的發育過程。PITX2的轉錄調節活性受到催乳素的調節。已發現人體內的PITX2有三種轉錄變體^[8]。

PITX2在發育中與左—右軸的建立及左右不對稱性的形成有關，比如左側中胚層（英語：lateral mesoderm）、心臟、肺、脾的不對稱發育及早起胃腸道的彎折。已證明在非人脊椎動物中，PITX2的同源基因亦有這樣的功能。敲除小鼠的Pitx2基因後，會導致身體左側器官形態發育異常。PITX2本身的表達受到ASE增強子和NODAL（英語：NODAL）蛋白的調控。目前的研究證據顯示NODAL蛋白主要調控頭部的PITX2基因表達，而ASE主要調控控制不對稱發展的PITX2基因的發展，如肝、脾的不對稱發展。在眼部發育中，PITX2能抑制眼外肌的自噬，並能控制其生長^[10]^[11]^[12]。PITX2的三種轉錄變體PITX2a、PITX2b、PITX2c各自都有不重疊的不同功能^[13]。

PITX2亦參與了附肢形態形成。PITX2能調控MyoD基因的表達，使其在附肢形成過程中一直表達。MyoD基因與骨骼形態發生有關。研究表明Pixt2在肌肉中先於MyoD表達。要激活MyoD基因表達，PITX2首先會募集到MyoD的核心增強子上，然後激活MyoD的表達。Myf5、Myf6基因亦能調控MyoD的表達，但與PITX2之間互不影響。PITX2對附肢發育的調控依賴PAX3蛋白。在缺乏PAX3的情況下，即使PITX2表達附肢也無法形成。該實驗結果提示在調控通路中PITX2處於PAX3的下游，充當了PAX3和MyoD之間的中間體。總而言之，PITX2在附肢發育中是不可或缺的^[14]。

另外，有證據表明Pitx2在大鼠體內與性腺生成障礙有關^[15]。

臨床意義

PITX2基因突變可能導致阿克森費爾德綜合徵（英語：Axenfeld-Rieger syndrome）（Axenfeld-Rieger syndrome, ARS）、虹膜發育不良綜合徵（英語：iridogoniodysgenesis, dominant type）（iridogoniodysgenesis syndrome, IGDS）等表現爲眼前間充質發育不良（英語：Anterior segment mesenchymal dysgenesis）的病徵^[8]。

在惡性腫瘤中，PITX2常常會過表達。比如，甲狀腺癌^[16]、卵巢癌^[17]和結腸癌^[18]的PITX2表達水平都高於正常的非腫瘤組織。研究人員推測，腫瘤細胞的PITX2表達異常開啓，造成了細胞的惡性增殖。此前的研究表明PITX2會調控C-Myc以及細胞週期蛋白D1、D2的表達，這些事實支持上述假說^[19]^[20]^[20]

研究表明，腎癌組織內，PITX2的表達能提高ABCB1（英語：ABCB1）基因的表達強度。進一步研究表明，PITX2能與ABCB1基因的啓動子結合，使該基因表達。該基因編碼的蛋白能夠轉運多種藥物，使細胞對化療藥物的耐藥性增強。如果降低腎癌細胞內PITX2的表達強度，那麼細胞的增殖速度會減緩，化療藥物多柔比星（doxorubicin）對細胞的殺傷力也會增加^[21]。

在人食管立方細胞瘤（esophageal squamous cell carcinoma（ESCC））中，PITX2的表達水平亦高於正常組織。臨床數據表明PITX2的表達強度與該腫瘤的擴散性成正比。患該癌症的病人，如果腫瘤PITX2表達強度較高，那麼對化療藥物會有較高的耐藥性.醫生因而可以通過PITX2的表達強度來預測食管立方細胞瘤病人接受化療後病情能得到多大程度的緩解^[22]。

PITX2的雜合突變可能導致法洛四聯症、室間隔缺損、房間隔缺損、大動脈轉位、心內膜缺損（英語：endocardial cushion defect）（ECD）等先天性心臟病^[23]^[24]^[25]。PITX2的突變是由可變剪接模式的改變引起。PITX2C的變體PITX2C對心血管發生最爲重要。如果該變體不表達，心血管發生就會出現問題。PITX2的一些突變會顯著降低PITX2的轉錄活性，以及PITX2和NKX2（英語：NKX2）（NKX2在心血管發生中也扮演重要角色）之間的協同活性^[23]。由PITX2突變產生的表型多樣，可能是由不同的遺傳背景、表觀遺傳修飾蛋白以及不同/延遲的外顯率造成^[24]。值得注意的是PITX2的突變並不是造成先天性心臟病的主導因素，但會影響這些疾病的發展^[25]。

參考

^ 與PITX2相關的疾病；在維基數據上查看/編輯參考.
^ ^2.0 ^2.1 ^2.2 GRCh38: Ensembl release 89: ENSG00000164093 - Ensembl, May 2017
^ ^3.0 ^3.1 ^3.2 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.
^ Arakawa H, Nakamura T, Zhadanov AB, Fidanza V, Yano T, Bullrich F, Shimizu M, Blechman J, Mazo A, Canaani E, Croce CM. 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. Apr 1998, 95 (8): 4573–8. PMC 22531 . PMID 9539779. doi:10.1073/pnas.95.8.4573.
^ Héon E, Sheth BP, Kalenak JW, Sunden SL, Streb LM, Taylor CM, Alward WL, Sheffield VC, Stone EM. Linkage of autosomal dominant iris hypoplasia to the region of the Rieger syndrome locus (4q25). Human Molecular Genetics. Aug 1995, 4 (8): 1435–9. PMID 7581385. doi:10.1093/hmg/4.8.1435.
^ ^8.0 ^8.1 ^8.2 Entrez Gene: PITX2 paired-like homeodomain transcription factor 2.
^ Logan M, Pagán-Westphal SM, Smith DM, Paganessi L, Tabin CJ. The transcription factor Pitx2 mediates situs-specific morphogenesis in response to left-right asymmetric signals. Cell. Aug 1998, 94 (3): 307–17. PMID 9708733. doi:10.1016/S0092-8674(00)81474-9.
^ Campione M, Steinbeisser H, Schweickert A, Deissler K, van Bebber F, Lowe LA, Nowotschin S, Viebahn C, Haffter P, Kuehn MR, Blum M. The homeobox gene Pitx2: mediator of asymmetric left-right signaling in vertebrate heart and gut looping. Development. Mar 1999, 126 (6): 1225–34. PMID 10021341.
^ Shiratori H, Yashiro K, Shen MM, Hamada H. Conserved regulation and role of Pitx2 in situs-specific morphogenesis of visceral organs. Development. Aug 2006, 133 (15): 3015–25. PMID 16835440. doi:10.1242/dev.02470.
^ Zacharias AL, Lewandoski M, Rudnicki MA, Gage PJ. Pitx2 is an upstream activator of extraocular myogenesis and survival. Developmental Biology. Jan 2011, 349 (2): 395–405. PMC 3019256 . PMID 21035439. doi:10.1016/j.ydbio.2010.10.028.
^ Essner JJ, Branford WW, Zhang J, Yost HJ. Mesendoderm and left-right brain, heart and gut development are differentially regulated by pitx2 isoforms. Development. Mar 2000, 127 (5): 1081–93. PMID 10662647.
^ L'honoré A, Ouimette JF, Lavertu-Jolin M, Drouin J. Pitx2 defines alternate pathways acting through MyoD during limb and somitic myogenesis. Development. Nov 2010, 137 (22): 3847–56. PMID 20978076. doi:10.1242/dev.053421.
^ Nandi SS, Ghosh P, Roy SS. Expression of PITX2 homeodomain transcription factor during rat gonadal development in a sexually dimorphic manner. Cellular Physiology and Biochemistry. 2011, 27 (2): 159–70. PMID 21325833. doi:10.1159/000325218.
^ Huang Y, Guigon CJ, Fan J, Cheng SY, Zhu GZ. Pituitary homeobox 2 (PITX2) promotes thyroid carcinogenesis by activation of cyclin D2. Cell Cycle. Apr 2010, 9 (7): 1333–41. PMID 20372070. doi:10.4161/cc.9.7.11126.
^ Fung FK, Chan DW, Liu VW, Leung TH, Cheung AN, Ngan HY. Increased expression of PITX2 transcription factor contributes to ovarian cancer progression. PLOS ONE. 2012, 7 (5): e37076. PMC 3352869 . PMID 22615897. doi:10.1371/journal.pone.0037076.
^ Hirose H, Ishii H, Mimori K, Tanaka F, Takemasa I, Mizushima T, Ikeda M, Yamamoto H, Sekimoto M, Doki Y, Mori M. The significance of PITX2 overexpression in human colorectal cancer. Annals of Surgical Oncology. Oct 2011, 18 (10): 3005–12. PMID 21479692. doi:10.1245/s10434-011-1653-z.
^ 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. Identification of a Wnt/Dvl/beta-Catenin --> Pitx2 pathway mediating cell-type-specific proliferation during development. Cell. Nov 2002, 111 (5): 673–85. PMID 12464179. doi:10.1016/s0092-8674(02)01084-x.
^ ^20.0 ^20.1 Baek SH, Kioussi C, Briata P, Wang D, Nguyen HD, Ohgi KA, Glass CK, Wynshaw-Boris A, Rose DW, Rosenfeld MG. 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. Mar 2003, 100 (6): 3245–3250. PMC 152277 . PMID 12629224. doi:10.1073/pnas.0330217100.
^ Lee WK, Chakraborty PK, Thévenod F. 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. Aug 2013, 133 (3): 556–67. PMID 23354914. doi:10.1002/ijc.28060.
^ 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. PITX2: a promising predictive biomarker of patients' prognosis and chemoradioresistance in esophageal squamous cell carcinoma. International Journal of Cancer. Journal International Du Cancer. Jun 2013, 132 (11): 2567–2577. PMID 23132660. doi:10.1002/ijc.27930.
^ ^23.0 ^23.1 Sun, Y. PITX2 loss-of-function mutation contributes to tetralogy of Fallot. Gene. 2016-02-15, 577: 258–264. PMID 26657035. doi:10.1016/j.gene.2015.12.001.
^ ^24.0 ^24.1 Zhao, C. PITX2 Loss-of-Function Mutation contributes to Congenital Endocardial Cushion Defect and Axenfold-Rieger Syndrome. PLOS ONE. 2015-04-20, 10: e0124409. PMC 4404345 . PMID 25893250. doi:10.1371/journal.pone.0124409.
^ ^25.0 ^25.1 Dong, Wei. Novel Pitx2c loss-of-function mutations associated with complex congenital heart disease. International Journal of Molecular Medicine. 2014-01-14. doi:10.3892/ijmm.2014.168.

拓展閱讀

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

外部連結

醫學主題詞表（MeSH）：PITX2+protein,+human

PITX2引用了美國國家醫學圖書館提供的資料，這些資料屬於公共領域。

[1] 與PITX2相關的疾病；在維基數據上查看/編輯參考.

[refGRCh38Ensembl-2] 2.0 ^2.1 ^2.2 GRCh38: Ensembl release 89: ENSG00000164093 - Ensembl, May 2017

[refGRCm38Ensembl-3] 3.0 ^3.1 ^3.2 GRCm38: Ensembl release 89: ENSMUSG00000028023 - Ensembl, May 2017

[4] Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[5] Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid9539779-6] Arakawa H, Nakamura T, Zhadanov AB, Fidanza V, Yano T, Bullrich F, Shimizu M, Blechman J, Mazo A, Canaani E, Croce CM. 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. Apr 1998, 95 (8): 4573–8. PMC 22531 . PMID 9539779. doi:10.1073/pnas.95.8.4573.

[pmid7581385-7] Héon E, Sheth BP, Kalenak JW, Sunden SL, Streb LM, Taylor CM, Alward WL, Sheffield VC, Stone EM. Linkage of autosomal dominant iris hypoplasia to the region of the Rieger syndrome locus (4q25). Human Molecular Genetics. Aug 1995, 4 (8): 1435–9. PMID 7581385. doi:10.1093/hmg/4.8.1435.

[entrez-8] 8.0 ^8.1 ^8.2 Entrez Gene: PITX2 paired-like homeodomain transcription factor 2.

[tabin-9] Logan M, Pagán-Westphal SM, Smith DM, Paganessi L, Tabin CJ. The transcription factor Pitx2 mediates situs-specific morphogenesis in response to left-right asymmetric signals. Cell. Aug 1998, 94 (3): 307–17. PMID 9708733. doi:10.1016/S0092-8674(00)81474-9.

[pmid10021341-10] Campione M, Steinbeisser H, Schweickert A, Deissler K, van Bebber F, Lowe LA, Nowotschin S, Viebahn C, Haffter P, Kuehn MR, Blum M. The homeobox gene Pitx2: mediator of asymmetric left-right signaling in vertebrate heart and gut looping. Development. Mar 1999, 126 (6): 1225–34. PMID 10021341.

[pmid16835440-11] Shiratori H, Yashiro K, Shen MM, Hamada H. Conserved regulation and role of Pitx2 in situs-specific morphogenesis of visceral organs. Development. Aug 2006, 133 (15): 3015–25. PMID 16835440. doi:10.1242/dev.02470.

[pmid21035439-12] Zacharias AL, Lewandoski M, Rudnicki MA, Gage PJ. Pitx2 is an upstream activator of extraocular myogenesis and survival. Developmental Biology. Jan 2011, 349 (2): 395–405. PMC 3019256 . PMID 21035439. doi:10.1016/j.ydbio.2010.10.028.

[pmid10662647-13] Essner JJ, Branford WW, Zhang J, Yost HJ. Mesendoderm and left-right brain, heart and gut development are differentially regulated by pitx2 isoforms. Development. Mar 2000, 127 (5): 1081–93. PMID 10662647.

[Pitx2_and_Myogenesis-14] L'honoré A, Ouimette JF, Lavertu-Jolin M, Drouin J. Pitx2 defines alternate pathways acting through MyoD during limb and somitic myogenesis. Development. Nov 2010, 137 (22): 3847–56. PMID 20978076. doi:10.1242/dev.053421.

[pmid21325833-15] Nandi SS, Ghosh P, Roy SS. Expression of PITX2 homeodomain transcription factor during rat gonadal development in a sexually dimorphic manner. Cellular Physiology and Biochemistry. 2011, 27 (2): 159–70. PMID 21325833. doi:10.1159/000325218.

[pmid20372070-16] Huang Y, Guigon CJ, Fan J, Cheng SY, Zhu GZ. Pituitary homeobox 2 (PITX2) promotes thyroid carcinogenesis by activation of cyclin D2. Cell Cycle. Apr 2010, 9 (7): 1333–41. PMID 20372070. doi:10.4161/cc.9.7.11126.

[17] Fung FK, Chan DW, Liu VW, Leung TH, Cheung AN, Ngan HY. Increased expression of PITX2 transcription factor contributes to ovarian cancer progression. PLOS ONE. 2012, 7 (5): e37076. PMC 3352869 . PMID 22615897. doi:10.1371/journal.pone.0037076.

[18] Hirose H, Ishii H, Mimori K, Tanaka F, Takemasa I, Mizushima T, Ikeda M, Yamamoto H, Sekimoto M, Doki Y, Mori M. The significance of PITX2 overexpression in human colorectal cancer. Annals of Surgical Oncology. Oct 2011, 18 (10): 3005–12. PMID 21479692. doi:10.1245/s10434-011-1653-z.

[pmid12464179-19] 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. Identification of a Wnt/Dvl/beta-Catenin --> Pitx2 pathway mediating cell-type-specific proliferation during development. Cell. Nov 2002, 111 (5): 673–85. PMID 12464179. doi:10.1016/s0092-8674(02)01084-x.

[ReferenceA-20] 20.0 ^20.1 Baek SH, Kioussi C, Briata P, Wang D, Nguyen HD, Ohgi KA, Glass CK, Wynshaw-Boris A, Rose DW, Rosenfeld MG. 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. Mar 2003, 100 (6): 3245–3250. PMC 152277 . PMID 12629224. doi:10.1073/pnas.0330217100.

[ReferenceB-21] Lee WK, Chakraborty PK, Thévenod F. 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. Aug 2013, 133 (3): 556–67. PMID 23354914. doi:10.1002/ijc.28060.

[Zhang_J_2577-22] 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. PITX2: a promising predictive biomarker of patients' prognosis and chemoradioresistance in esophageal squamous cell carcinoma. International Journal of Cancer. Journal International Du Cancer. Jun 2013, 132 (11): 2567–2577. PMID 23132660. doi:10.1002/ijc.27930.

[:0-23] 23.0 ^23.1 Sun, Y. PITX2 loss-of-function mutation contributes to tetralogy of Fallot. Gene. 2016-02-15, 577: 258–264. PMID 26657035. doi:10.1016/j.gene.2015.12.001.

[:1-24] 24.0 ^24.1 Zhao, C. PITX2 Loss-of-Function Mutation contributes to Congenital Endocardial Cushion Defect and Axenfold-Rieger Syndrome. PLOS ONE. 2015-04-20, 10: e0124409. PMC 4404345 . PMID 25893250. doi:10.1371/journal.pone.0124409.

[:2-25] 25.0 ^25.1 Dong, Wei. Novel Pitx2c loss-of-function mutations associated with complex congenital heart disease. International Journal of Molecular Medicine. 2014-01-14. doi:10.3892/ijmm.2014.168.

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