This proposal is concerned with two characteristics that we have found most relevant to transformation: 1) activation consequences of erbB signaling complexes and 2) the physical interactions and linkage of the erbB transforming machinery to certain protein elements of the centrosome that guide mitosis and cytokinesis. These studies are an extension of previously funded efforts to understand the erbB receptor assembly and specific signaling events that emanate from an active or inactive receptor complex. We have found that a malignant tumor cell could be rendered more normal by disabling the erbB receptor complex with monoclonal antibodies or mimetics. Reversal of phenotype occurred in malignant cells with multiple abnormal centrosomes. Moreover, we have now found that activated p185-EGFR heteromeric receptor complexes lead to elevated levels of Survivin, a protein associated with the centrosome. We were successful in cloning a novel gene, Su48, which encodes a centrosome-associated protein that physically associates with Survivin. Su48 is highly expressed in a number of tumor cell lines. Ectopic expression of Su48 and its mutant forms can cause abnormal mitosis and abnormal DNA content which correlates with aneuploidy (Rapi, et al. 1996). We hypothesize that disruption of normal Su48 functions causes centrosome dysfunction and abnormal spindle formation. This process contributes to aberrant distribution of chromosomes and progressive malignant transformation. We have found that Su48 associates with specific kinases and proteins that are relevant to mitosis and accumulation of genetic abnormalities. In the proposed studies we will examine features of receptor complex formation that are essential as a transforming mechanism in breast tumors. Next, we will define the molecular functions of Su48 during centrosome duplication, spindle formation, and cytokinesis. In addition, we will investigate the role of Su48 in malignant transformation. Collectively, the studies will analyze certain properties of the signaling complex and associated novel proteins that are part of the centrosome. These studies will improve our understanding of the roles of Su48 in mitosis and cancer development. Characterization of Su48 and its related signaling molecules may provide novel markers for early detection and diagnosis of breast cancers as well as new targets for therapy. ? ?
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