INTESTINAL CELL GROWTH CONTROL--ROLE OF TYROSINE KINASE

对肠道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涉及一系列复杂的 分子事件。我们的目标是确定pp60c-scr的作用。 以及相关的蛋白酪氨酸激酶参与这一调控过程。 从历史上看，pp60src升高之间存在很强的相关性 激酶活性与细胞转化。我们确定pp60c-src 从人类结肠癌、恶性大肠息肉和 良性息肉发生癌症的风险最大，有更高的 比活力高于正常粘膜的pp60c-src。我们的结果也是 显示pp60c-src活性随着原代细胞的分化而降低 沿着鸡肠的隐窝-绒毛轴。总而言之，数据 提示c-src的下调对分化很重要， 而c-src的解除调控对肠道的转化非常重要。 上皮细胞。 我们将研究调节肠道pp60c-src活性的机制。 细胞。我们和其他人已经确定了三种监管机制 其他细胞中pp60c-src的活性：pp60c-src的磷酸化， Pp60c-src与另一种蛋白质的关联，或 C-src的编码区。已知的翻译后事件 改变pp60c-src活性将在隐窝绒毛沿线的细胞中进行研究。 鸡肠轴。C-src将从结肠癌中分离出来。 其中pp60c-src活性升高，其编码区 分析了体细胞突变并检测了致癌潜力 成纤维细胞。Ppp60c-src活性将在 溃疡性结肠炎患者，就像腺瘤性息肉一样， 可能是恶性的。最后，pp60c-src的活性与 将测量酪氨酸激酶和酪氨酸激酶的底物 将在结肠癌细胞中被鉴定。 我们的目的是了解pp60c-src和相关的激酶在 调节肠道细胞的生长。通过解决基本机制 在正常细胞中的生长控制，我们可以阐明致病原因 人类疾病的机制，即结肠癌的发生。我们希望 找出扰乱正常调控途径的早期事件 大肠息肉和溃疡性结肠炎的癌前病变粘膜。这个 结果将对结肠的预防、诊断和治疗产生影响 癌症。

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.