Grupo de Carcinogénesis Epitelial, Programa de Patología Molecular, CNIO-Spanish National Cancer Research Center, 28029 Madrid, Spain.
Biochem J. 2013 May 1;451(3):395-405. doi: 10.1042/BJ20120873.
The PTF1 (pancreas transcription factor 1) complex is a master regulator of differentiation of acinar cells, responsible for the production of digestive enzymes. In the adult pancreas, PTF1 contains two pancreas-restricted transcription factors: Ptf1a and Rbpjl. PTF1 recruits P/CAF [p300/CREB (cAMP-response-element-binding protein)-binding protein-associated factor] which acetylates Ptf1a and enhances its transcriptional activity. Using yeast two-hybrid screening, we identified ICAT (inhibitor of β-catenin and Tcf4) as a novel Ptf1a interactor. ICAT regulates the Wnt pathway and cell proliferation. We validated and mapped the ICAT-Ptf1a interaction in vitro and in vivo. We demonstrated that, following its overexpression in acinar tumour cells, ICAT regulates negatively PTF1 activity in vitro and in vivo. This effect was independent of β-catenin and was mediated by direct binding to Ptf1a and displacement of P/CAF. ICAT also modulated the expression of Pdx1 and Sox9 in acinar tumour cells. ICAT overexpression reduced the interaction of Ptf1a with Rbpjl and P/CAF and impaired Ptf1a acetylation by P/CAF. ICAT did not affect the subcellular localization of Ptf1a. In human pancreas, ICAT displayed a cell-type-specific distribution; in acinar and endocrine cells, it was nuclear, whereas in ductal cells, it was cytoplasmic. In ductal adenocarcinomas, ICAT displayed mainly a nuclear or mixed distribution and the former was an independent marker of survival. ICAT regulates acinar differentiation and it does so through a novel Wnt pathway-independent mechanism that may contribute to pancreatic disease.
PTF1（胰腺转录因子 1）复合物是胰腺腺泡细胞分化的主要调节因子，负责消化酶的产生。在成人胰腺中，PTF1 包含两种胰腺特异性转录因子：Ptf1a 和 Rbpjl。PTF1 招募 P/CAF（p300/CREB（cAMP 反应元件结合蛋白）结合蛋白相关因子），其使 Ptf1a 乙酰化并增强其转录活性。通过酵母双杂交筛选，我们鉴定出 ICAT（β-catenin 和 Tcf4 的抑制剂）为 Ptf1a 的一种新型相互作用蛋白。ICAT 调节 Wnt 通路和细胞增殖。我们在体外和体内验证并绘制了 ICAT-Ptf1a 相互作用图。我们证明，在胰腺腺泡肿瘤细胞中过表达后，ICAT 负调控体外和体内的 PTF1 活性。这种作用独立于 β-catenin，通过与 Ptf1a 的直接结合和 P/CAF 的置换来介导。ICAT 还调节胰腺腺泡肿瘤细胞中 Pdx1 和 Sox9 的表达。ICAT 过表达减少了 Ptf1a 与 Rbpjl 和 P/CAF 的相互作用，并损害了 P/CAF 对 Ptf1a 的乙酰化作用。ICAT 不影响 Ptf1a 的亚细胞定位。在人胰腺中，ICAT 显示出细胞类型特异性分布；在腺泡和内分泌细胞中，它是核内的，而在导管细胞中，它是细胞质的。在胰腺导管腺癌中，ICAT 主要显示核内或混合分布，前者是独立的生存标志物。ICAT 调节胰腺腺泡细胞分化，其通过一种新的非 Wnt 通路机制起作用，可能有助于胰腺疾病的发生。
