APC control of intestinal differentiation

APC 控制肠道分化

• 批准号: 7786717
• 负责人: DAVID A JONES
• 金额: $ 21.62万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-12 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7786717
• 关键词: Acids; Anabolism; Biological Models; C-terminal binding protein; Carcinoma; 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; Mus; Mutation; Nuclear; Nuclear Translocation; Oncogenes; Oncogenic; Patients; Polyps; Pongidae; Preventive; Protein C; 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.

我们已经证明，人类结肠腺瘤和癌显示出维甲酸生物合成酶的严重缺乏，并且APC通过控制视黄醇脱氢酶的表达来控制肠细胞分化。这些发现提示了一种新的模型，其中APC通过控制维甲酸的生物合成来促进肠细胞分化，并表明APC的功能不仅限于其在调节典型WNT信号传导中的作用。在机制上，我们已经确定了转录共抑制因子c端结合蛋白（CtBP），作为一种新型的apc调节蛋白，可以抑制视黄醇脱氢酶和肠细胞分化。与APC对CtBP的控制一致，取自FAP患者的人腺瘤与邻近的、未受损伤的组织相比，显示出强大的核CtBP染色。然而，令人惊讶的是，这些相同的切片几乎没有显示核B-catenin的证据，这表明CtBP的积累可能先于B-catenin的核积累，并且B-catenin的核积累可能需要APC损失之外的事件。与这种可能性相一致的是，许多报告显示，b -连环蛋白信号在小腺瘤和大腺瘤中的激活似乎与k-ras癌基因的激活突变相似。此外，在携带人类FAP中发现的典型突变的小鼠中进行的研究表明，k-ras的激活增加了息肉的大小和数量。这些数据表明，在大腺瘤形成过程中，k-ras激活允许b -连环蛋白刺激的肠细胞增殖。事实上，我们的初步数据表明，单靠APC的丢失不足以促进斑马鱼肠细胞的增殖。此外，在人类细胞和斑马鱼中，致癌的k-ras促进核b -连环蛋白的积累和随后的增殖。我们对FAP和未定义高风险家族的研究，以及我们在使用斑马鱼作为遗传模型系统研究APC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在结肠腺瘤的发生和发展中的作用。