PITX2

PITX2
已知的结构
PDB	直系同源搜索: PDBe RCSB
PDBID列表
	2L7F、2L7M、2LKX
识别号
别名	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
相关疾病
	Axenfeld-Rieger syndrome type 1、虹膜发育不良综合征、ring dermoid of cornea、Rieger anomaly
基因位置（人类）
染色体	4号染色体
终止	110,642,123 bp
基因位置（小鼠）
染色体	小鼠3号染色体
终止	129,013,240 bp
RNA表达模式
	查阅更多表达数据
基因本体
分子功能	• 相同蛋白质结合; • protein homodimerization activity; • transcription cis-regulatory region binding; • sequence-specific DNA binding; • DNA结合; • 转录共激活因子活性; • chromatin DNA binding; • DNA-binding transcription activator activity, RNA polymerase II-specific; • 血浆蛋白结合; • RNA polymerase II cis-regulatory region sequence-specific DNA binding; • chromatin binding; • ribonucleoprotein complex binding; • DNA结合转录因子活性; • DNA结合转录阻遏物活性，RNA聚合酶II特异性; • 转录因子结合; • 磷蛋白结合; • DNA-binding transcription factor activity, RNA polymerase II-specific;
细胞组分	• 细胞核; • 细胞质; • 转录调节复合物; • 核质;
生物学过程	• 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; • 垂体的发生; • 血管发生; • regulation of cell population proliferation; • myoblast fusion; • hair cell differentiation; • 脾的发生; • 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; • 心脏发育; • 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信号通路; • 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
	维基数据
查看/编辑人类	查看/编辑小鼠

PITX2（Paired-like homeodomain transcription factor 2（类成对同源框转录因子2）/pituitary homeobox 2（垂体同源框2））是一个位于人第四号染色体上的基因，由其编码的蛋白为PITX2^[6]^[7]^[8]。

功能

PITX2蛋白属于RIEG/PITX同源框蛋白家族，有一个属于Bicoid（英语：Bicoid）蛋白家族的同源结构域。从功能上说，PITX2是一种转录因子^[9]，主要调控前胶原赖氨酰羟化酶（英语：lysyl hydroxylase）（procollagen lysyl hydroxylase）基因的表达。赖氨酰羟化酶参与眼、牙，以及腹部器官的发育过程。PITX2的转录调节活性受到催乳素的调节。已发现人体内的PITX2有三种转录变体^[8]。

PITX2在发育中与左—右轴的建立及左右不对称性的形成有关，比如左侧中胚层（英语：lateral mesoderm）、心脏、肺、脾的不对称发育及早起胃肠道的弯折。已证明在非人脊椎动物中，PITX2的同源基因亦有这样的功能。敲除小鼠的Pitx2基因后，会导致身体左侧器官形态发育异常。PITX2本身的表达受到ASE增强子和NODAL（英语：NODAL）蛋白的调控。目前的研究证据显示NODAL蛋白主要调控头部的PITX2基因表达，而ASE主要调控控制不对称发展的PITX2基因的发展，如肝、脾的不对称发展。在眼部发育中，PITX2能抑制眼外肌的自噬，并能控制其生长^[10]^[11]^[12]。PITX2的三种转录变体PITX2a、PITX2b、PITX2c各自都有不重叠的不同功能^[13]。

PITX2亦参与了附肢形态形成。PITX2能调控MyoD基因的表达，使其在附肢形成过程中一直表达。MyoD基因与骨骼形态发生有关。研究表明Pixt2在肌肉中先于MyoD表达。要激活MyoD基因表达，PITX2首先会募集到MyoD的核心增强子上，然后激活MyoD的表达。Myf5、Myf6基因亦能调控MyoD的表达，但与PITX2之间互不影响。PITX2对附肢发育的调控依赖PAX3蛋白。在缺乏PAX3的情况下，即使PITX2表达附肢也无法形成。该实验结果提示在调控通路中PITX2处于PAX3的下游，充当了PAX3和MyoD之间的中间体。总而言之，PITX2在附肢发育中是不可或缺的^[14]。

另外，有证据表明Pitx2在大鼠体内与性腺生成障碍有关^[15]。

临床意义

PITX2基因突变可能导致阿克森费尔德综合征（英语：Axenfeld-Rieger syndrome）（Axenfeld-Rieger syndrome, ARS）、虹膜发育不良综合征（英语：iridogoniodysgenesis, dominant type）（iridogoniodysgenesis syndrome, IGDS）等表现为眼前间充质发育不良（英语：Anterior segment mesenchymal dysgenesis）的病征^[8]。

在恶性肿瘤中，PITX2常常会过表达。比如，甲状腺癌^[16]、卵巢癌^[17]和结肠癌^[18]的PITX2表达水平都高于正常的非肿瘤组织。研究人员推测，肿瘤细胞的PITX2表达异常开启，造成了细胞的恶性增殖。此前的研究表明PITX2会调控C-Myc以及细胞周期蛋白D1、D2的表达，这些事实支持上述假说^[19]^[20]^[20]

研究表明，肾癌组织内，PITX2的表达能提高ABCB1（英语：ABCB1）基因的表达强度。进一步研究表明，PITX2能与ABCB1基因的启动子结合，使该基因表达。该基因编码的蛋白能够转运多种药物，使细胞对化疗药物的耐药性增强。如果降低肾癌细胞内PITX2的表达强度，那么细胞的增殖速度会减缓，化疗药物多柔比星（doxorubicin）对细胞的杀伤力也会增加^[21]。

在人食管立方细胞瘤（esophageal squamous cell carcinoma（ESCC））中，PITX2的表达水平亦高于正常组织。临床数据表明PITX2的表达强度与该肿瘤的扩散性成正比。患该癌症的病人，如果肿瘤PITX2表达强度较高，那么对化疗药物会有较高的耐药性.医生因而可以通过PITX2的表达强度来预测食管立方细胞瘤病人接受化疗后病情能得到多大程度的缓解^[22]。

PITX2的杂合突变可能导致法洛四联症、室中隔缺损、房中隔缺损、大动脉转位、心内膜缺损（英语：endocardial cushion defect）（ECD）等先天性心脏病^[23]^[24]^[25]。PITX2的突变是由可变剪接模式的改变引起。PITX2C的变体PITX2C对心血管发生最为重要。如果该变体不表达，心血管发生就会出现问题。PITX2的一些突变会显著降低PITX2的转录活性，以及PITX2和NKX2（英语：NKX2）（NKX2在心血管发生中也扮演重要角色）之间的协同活性^[23]。由PITX2突变产生的表型多样，可能是由不同的遗传背景、表观遗传修饰蛋白以及不同/延迟的外显率造成^[24]。值得注意的是PITX2的突变并不是造成先天性心脏病的主导因素，但会影响这些疾病的发展^[25]。

参考

^ 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.

拓展阅读

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.

外部链接

医学主题词表（MeSH）：PITX2+protein,+human

PITX2引用了美国国家医学图书馆提供的数据，这些数据属于公共领域。

[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.

[6]

[7]

[8]

[1]

[2]

[3]

[4]

[5]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]