PITX2

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。 PITX2蛋白屬於RIEG/PITX同源框蛋白家族，有一個屬於Bicoid（英语：Bicoid）蛋白家族的同源結構域。從功能上說，PITX2是一種轉錄因子，主要調控前膠原賴氨酰羥化酶（英语：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。 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（英语：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（英语：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。PITX2的三種轉錄變體PITX2a、PITX2b、PITX2c各自都有不重疊的不同功能。 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。 另外，有證據表明Pitx2在大鼠體內與性腺生成障礙有關。 PITX2基因突變可能導致阿克森費爾德綜合徵（英语：Axenfeld-Rieger syndrome）（Axenfeld-Rieger syndrome, ARS）、虹膜發育不良綜合徵（英语：iridogoniodysgenesis, dominant type）（iridogoniodysgenesis syndrome, IGDS）等表現爲眼前間充質發育不良（英语：Anterior segment mesenchymal dysgenesis）的病徵。 在惡性腫瘤中，PITX2常常會過表達。比如，甲狀腺癌、 卵巢癌和結腸癌的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 研究表明，腎癌組織內，PITX2的表達能提高ABCB1（英语：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。 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。 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（英语：endocardial cushion defect）（ECD）等先天性心臟病。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（英语：NKX2）（NKX2在心血管發生中也扮演重要角色）之間的協同活性。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。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。 與PITX2相關的疾病；在維基數據上查看/編輯參考.  GRCh38: Ensembl release 89: ENSG00000164093 - Ensembl, May 2017 GRCm38: Ensembl release 89: ENSMUSG00000028023 - Ensembl, May 2017 Human PubMed Reference:. 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