Functional Study of a Carcinoma Associated Mucin MUC1

描述（由申请人提供）：MUC 1是一种肿瘤抗原，在大多数癌症中过表达，包括90%以上的乳腺癌。这种细胞相关粘蛋白是高度O-糖基化的，在正常分泌上皮组织中以低水平表达。MUC 1表达大大增加，并且在肿瘤和转移中细胞定位改变，其中发现MUC 1围绕整个细胞。虽然MUC 1不具有激酶活性，但胞质尾区与多种信号传导和粘附调节蛋白相互作用。这些蛋白质包括EGFR、erbB 2、3和4、蛋白激酶C δ、c-src、GSK 3 β、p120 ctn、β-连环蛋白和Grb 2。我们假设MUC 1作为一种衔接蛋白，将激酶、磷酸酶和其他衔接蛋白聚集在一起，组装成一种复合物，导致肿瘤形成，可能是通过诱导有丝分裂和/或细胞粘附状态的变化。小鼠乳腺中MUC 1的过表达，以模仿在人类中所看到的，导致63%的小鼠随机肿瘤形成。90%的肿瘤转移到肺部。在野生型小鼠或表达MUC 1但缺乏胞质尾的小鼠中未观察到肿瘤，表明胞质尾对功能至关重要。为了进一步表征MUC 1在乳腺和其他上皮组织中的致癌功能，我们提出：1）确定肿瘤发生中涉及的MUC 1蛋白的关键部分并定义下游信号传导途径，2）确定MUC 1胞质尾中特异性酪氨酸的作用，3）表征胞质尾与信号传导和肿瘤抑制蛋白的额外相互作用，和4）确定MUC 1在乳腺以外的组织中是否是致癌的。这些研究将显著增加我们对MUC 1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.