INTESTINAL CELL GROWTH CONTROL--ROLE OF TYROSINE KINASE

肠细胞生长的调节和这种调节的丧失 在细胞恶性转化过程中， 分子事件 我们的目标是确定pp 60 c-scr 和相关的蛋白酪氨酸激酶。 从历史上看，pp 60 src升高与 激酶活性和细胞转化。 我们确定pp 60 c-src 分离自人结肠癌、恶性结肠息肉，和 良性息肉发展成癌症的风险最大， 比正常粘膜的pp 60 c-src的活性高。 我们的研究结果还 显示pp 60 c-src活性随着原代细胞分化而降低 沿着鸡肠腺-绒毛轴。 在一起， 提示c-src下调对于分化是重要的， c-src的失调对肠上皮细胞的转化有重要作用 上皮细胞 我们将研究在肠道中调节pp 60 c-src活性的机制， 细胞 我们和其他人已经确定了三种调节机制， 其它细胞中的pp 60 c-src活性：pp 60 c-src的磷酸化， pp 60 c-src与另一种蛋白质的结合，或pp 60 c-src内的突变， c-src的编码区。 已知的翻译后事件 改变pp 60 c-src活性将在沿着隐窝绒毛的细胞中进行研究 鸡肠轴。c-src将从结肠癌中分离 其具有升高的pp 60 c-src活性，并且其编码区将被 分析了体细胞突变，并测试了致癌潜力， 成纤维细胞pp 60 c-src活性将在结肠粘膜中测量， 溃疡性结肠炎患者，像腺瘤性息肉一样， 恶性潜力。 最后，对pp 60 c-src的活性进行了相关分析， 将测量酪氨酸激酶，并且酪氨酸激酶的底物 将在结肠癌细胞中被鉴定。 我们的目的是了解pp 60 c-src和相关激酶在 调节肠细胞的生长。 通过解决基本机制 正常细胞的生长控制，我们可以阐明致病性 人类疾病的机制，即结肠癌的发生。 我们希望 确定干扰正常调节途径的早期事件， 结肠息肉和溃疡性结肠炎的癌前粘膜。 的 结果将影响结肠癌的预防、诊断和治疗 癌

Regulation of intestinal cell growth and the loss of that regulation during malignant transformation of cells involves a complex series of molecular events. Our objective is to determine the role of pp60c-scr and related protein-tyrosine kinases in this regulatory process. Historically, a strong correlation exists between elevated pp60src kinase activity and cell transformation. We determined that pp60c-src isolated from human colon carcinomas, malignant colonic polyps, and benign polyps at greatest risk for developing cancer, has higher specific activity than pp60c-src from normal mucosa. Our results also show that pp60c-src activity decreases as primary cells differentiate along the crypt-villus axis of chicken intestine. Together, the data suggest that down-regulation of c-src is important for differentiation, and deregulation of c-src is important for transformation of intestinal epithelia. We will study mechanisms that regulate pp60c-src activity in intestinal cells. We, and others, have identified three mechanisms that regulate pp60c-src activity in other cells: phosphorylation of pp60c-src, association of pp60c-src with another protein, or mutation within the coding region of c-src. Posttranslational events that are known to alter pp60c-src activity will be studied in cells along the crypt-villus axis of chicken intestine. c-src will be isolated from colon carcinomas which have elevated pp60c-src activity, and its coding region will be analyzed for somatic mutations and tested for oncogenic potential in fibroblasts. pp60c-src activity will be measured in colonic mucosa of patients with ulcerative colitis which, like adenomatous polyps, has malignant potential. Finally, the activity of pp60c-src -related tyrosine kinases will be measured and the substrates of tyrosine kinases will be identified in colon carcinoma cells. Our aim is to understand the role of pp60c-src and related kinases in regulating growth of intestinal cells. By addressing basic mechanisms of growth control in normal cells, we can elucidate pathogenic mechanisms in human disease, namely, colonic carcinogenesis. We hope to identify early events that perturb normal regulatory pathways in the precancerous mucosa of colonic polyps and ulcerative colitis. The results will impact on prevention, diagnosis and treatment of colon cancer.