Adenomatous polyposis coli control of C-terminal binding protein-1 stability regulates expression of intestinal retinol dehydrogenases
Adenomatous polyposis coli control of C-terminal binding protein-1 stability regulates expression of intestinal retinol dehydrogenases
复制标题
DOI：
10.1074/jbc.m602119200
复制
发表时间：
2006-12-08
影响因子：
4.8
通讯作者：
Jones, David A.
中科院分区：
文献类型：
--
作者：
Nadauld, Lincoln D.;Phelps, Reid;Jones, David A.
人类腺瘤性结肠息肉病 (APC) 基因的突变被认为会引发结直肠肿瘤的发生。 APC 的肿瘤抑制功能主要归因于其通过靶向破坏 β-catenin 来调节 WNT 通路的能力。我们在此报告了 APC 通过蛋白酶体依赖性过程调节转录共阻遏物 C 末端结合蛋白 1 (CtBP1) 降解的新作用。此外，CtBP1 还能抑制肠道视黄醇脱氢酶的表达，而视黄醇脱氢酶是视黄酸生产和肠道分化所必需的。与匹配的未受累组织相比，取自家族性腺瘤性息肉病个体的腺瘤含有高水平的 CtBP1 蛋白，这支持了 CtBP1 在结直肠癌发生中的作用。 APC 和 CtBP1 之间的关系在人类和斑马鱼之间是保守的，并提供了解释 APC 对肠道视黄酸生物合成的控制的机制模型。
Mutations in the human adenomatous polyposis coli (APC) gene are thought to initiate colorectal tumorigenesis. The tumor suppressor function of APC is attributed primarily to its ability to regulate the WNT pathway by targeting the destruction of beta-catenin. We report here a novel role for APC in regulating degradation of the transcriptional co-repressor C-terminal-binding protein-1 (CtBP1) through a proteasome-dependent process. Further, CtBP1 suppresses the expression of intestinal retinol dehydrogenases, which are required for retinoic acid production and intestinal differentiation. In support of a role for CtBP1 in initiation of colorectal cancer, adenomas taken from individuals with familial adenomatous polyposis contain high levels of CtBP1 protein in comparison with matched, uninvolved tissue. The relationship between APC and CtBP1 is conserved between humans and zebrafish and provides a mechanistic model explaining APC control of intestinal retinoic acid biosynthesis.