APC control of intestinal differentiation

APC 控制肠道分化

• 批准号: 8449514
• 负责人: DAVID A JONES
• 金额: $ 27.67万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449514
• 关键词: Acids; Anabolism; Biological Models; C-terminal binding protein; Cell Differentiation process; Cell Proliferation; Cells; Clinical; Colon Carcinoma; Colonic Adenoma; Complex; Data; Development; Enterocytes; Enzymes; Event; Family; Funding; Genetic Models; Goals; Human; Intestines; KRAS2 gene; Measures; Modeling; Molecular; Mus; Mutation; Nuclear; Nuclear Translocation; Oncogenes; Oncogenic; Patients; Polyps; Pongidae; Preventive; Proteins; Regulation; Reporting; Retinol dehydrogenase; Role; Signal Transduction; Staining method; Stains; Testing; Tissues; Tretinoin; WNT Signaling Pathway; Work; Zebrafish; adenoma; high risk; innovation; intestinal epithelium; neoplastic; novel; prevent; ras Oncogene

We have shown that human colon adenomas and carcinomas show a profound deficiency of retinoic acid biosynthetic enzymes and that APC controls intestinal cell differentiation by controlling the expression of retinol dehydrogenases. These findings suggest a novel model wherein APC promotes enterocyte differentiation by controlling retinoic acid biosynthesis and indicates that the functions of APC are not limited to its well-established role in regulating canonical WNT signaling. Mechanistically, we have identified the transcriptional co-repressor, C-terminal binding protein (CtBP), as a novel, APC-regulated protein that suppresses retinol dehydrogenases and intestinal cell differentiation. Consistent with APC control of CtBP, human adenomas taken from FAP patients showed robust staining for nuclear CtBP in comparison to adjacent, uninvolved tissues. Surprisingly, however, these same sections showed little evidence of nuclear B-catenin suggesting that accumulation of CtBP may precede nuclear accumulation of B-catenin and that nuclear accumulation of B-catenin may require events in addition to loss of APC. Consistent with this possibility are a number of reports showing that activation of (B-catenin signaling in small versus large adenomas appears to parallel activating mutations in the k-ras oncogene. Further, work in mice carrying a mutation typical of those found in human FAP has shown that activation of k-ras increased polyp size and number. These data suggest that k-ras activation permits B-catenin-stimulated intestinal cell proliferation during the formation of a large adenoma. Indeed our preliminary data show that APC loss alone is insufficient to promote intestinal cell proliferation in zebrafish. Furthermore, oncogenic k-ras promotes the accumulation of nuclear B-catenin and subsequent proliferation in both human cells and zebrafish. Our access to both FAP and undefined high-risk families, as well as our expertise in using zebrafish as a genetic model system to study APC, provides us a unique opportunity to evaluate the contribution of CtBP and k-ras in the initiation and progression of colon adenomas.

我们已经表明，人类结肠腺瘤和癌显示出视黄酸生物合成酶的严重缺乏，APC通过控制视黄醇脱氢酶的表达来控制肠细胞分化。这些发现表明了一种新的模型，其中APC通过控制视黄酸生物合成来促进肠上皮细胞分化，并表明APC的功能并不限于其在调节经典WNT信号传导中的既定作用。从机制上讲，我们已经确定了转录辅阻遏物，C-末端结合蛋白（CtBP），作为一种新的，APC调节的蛋白质，抑制视黄醇脱氢酶和肠细胞分化。与CtBP的APC控制一致，与邻近的未受累组织相比，取自FAP患者的人腺瘤显示出对核CtBP的强染色。然而，令人惊讶的是，这些相同的切片几乎没有显示出核B-连环蛋白的证据，这表明CtBP的积累可能先于B-连环蛋白的核积累，并且B-连环蛋白的核积累可能需要除了APC丢失之外的事件。与这种可能性相一致的是，许多报告显示，在小腺瘤与大腺瘤中β-连环蛋白信号的激活似乎与k-ras癌基因的激活突变平行。此外，在携带人类FAP中发现的典型突变的小鼠中的工作表明，k-ras的激活增加了息肉的大小和数量。这些数据表明，k-ras激活允许B-连环蛋白刺激的肠细胞增殖过程中形成一个大的腺瘤。事实上，我们的初步数据表明，APC损失单独是不足以促进斑马鱼肠细胞增殖。此外，致癌的k-ras促进细胞核B-连环蛋白的积累和随后的人类细胞和斑马鱼的增殖。我们对FAP和未定义的高风险家族的访问，以及我们在使用斑马鱼作为研究APC的遗传模型系统方面的专业知识，为我们提供了一个独特的机会来评估CtBP和k-ras在结肠腺瘤的启动和进展中的贡献。