Functional Study of a Carcinoma Associated Mucin MUC1

描述(申请人提供)：MUC1是一种肿瘤抗原，在大多数癌症上过度表达，包括90%以上的乳腺癌。这种细胞相关的粘蛋白是高度O-糖基化的，在正常的分泌上皮组织中低水平表达。在肿瘤和转移瘤中，MUC1的表达大大增加，细胞定位发生改变，在肿瘤和转移瘤中，它被发现在整个细胞周围。虽然MUC1不具有激酶活性，但胞质尾巴与多种信号和黏附调节蛋白相互作用。这些蛋白包括EGFR、erbB2、3和4、蛋白激酶C Delta、c-src、GSK3β、p120 CTN、β-catenin和Grb2。我们假设MUC1作为一种接头蛋白，将激酶、磷酸酶和其他接头蛋白聚集在一起，组装成一个复合体，可能通过诱导有丝分裂和/或细胞黏附状态的改变而导致肿瘤的形成。在小鼠乳腺中过表达MUC1，以模拟在人类中看到的情况，导致63%的小鼠随机形成肿瘤。90%的肿瘤转移到肺部。在野生型小鼠或表达MUC1的小鼠中没有观察到肿瘤，这表明细胞质尾巴对功能至关重要。为了进一步研究MUC1在乳腺和其他上皮组织中的致癌功能，我们建议：1)确定参与肿瘤发生的MUC1蛋白的关键部分，并确定下游信号通路；2)确定特定酪氨酸在MUC1细胞质尾部中的作用；3)表征细胞质尾部与信号和肿瘤抑制蛋白的额外相互作用；以及4)确定MUC1是否在乳腺以外的组织中是致癌的。这些研究将大大加深我们对MUC1功能在上皮性肿瘤转化、生长、侵袭和转移过程中的重要性的理解。

DESCRIPTION (provided by applicant): MUC1 is a tumor antigen that is overexpressed on most carcinomas, including greater than 90% of breast carcinomas. This cell associated mucin is highly O-glycosylated and expressed at low levels on normal secretory epithelial tissues. MUC1 expression is greatly increased and the cellular localization is altered in tumors and metastases, where it is found surrounding the entire cell. Although MUC1 does not possess kinase activity, the cytoplasmic tail interacts with multiple signaling and adhesion-regulating proteins. Among these proteins are EGFR, erbB2, 3, and 4, Protein Kinase C delta, c-src, GSK3beta, p120 ctn, beta-catenin, and Grb2. We hypothesize that MUC1 serves as an adaptor protein that brings together kinases, phosphatases, and other adaptor proteins to assemble a complex that leads to tumor formation, possibly by inducing mitogenesis, and/or changes in the adhesive state of the cell. Overexpression of MUC1 in the mouse mammary gland, to mimic what is seen in humans, resulted in stochastic tumor formation in 63% of mice. Ninety percent of tumors metastasized to the lung. No tumors were observed in wildtype mice or mice expressing MUC1 lacking the cytoplasmic tail, suggesting that the cytoplasmic tail is critical to the function. To further characterize the oncogenic function of MUC1 in the mammary gland and other epithelial tissues, we propose: 1) to determine the critical portions of the MUC1 protein involved in tumorigenesis and define down-stream signaling pathways, 2) to determine the role of specific tyrosines in the MUC1 cytoplasmic tail, 3) to characterize additional interactions of the cytoplasmic tail with signaling and tumor suppressor proteins, and 4) to determine if MUC1 is oncogenic in tissues other than the mammary gland. These studies will significantly increase our understanding of the importance of MUC1 function in epithelial tumors during transformation, growth, invasion and metastasis.