Brain tumors are one of the leading causes of death among young children and adults. Glioblastomas are the most common primary brain tumors and are among the deadliest of tumors. However, how normal brain astrocytes develop into glioblastoma still remains a mystery. Identification and characterization of genes which can suppress tumor growth may eventually provide a rational basis for early detection and treatment of human glioblastoma. The PI recently found that cx43 can reverse the transformed phenotype of human glioblastomas. Furthermore, over-expression of cx43 significantly enhances apoptosis in low serum conditions and in response to chemotherapeutic agents. Furthermore, expression of cx43 leads to down-regulation of bc1-2 expression. The goals in this grant application are to analyze the molecular mechanisms of tumor suppression activity in relation to apoptosis by cx43. The projects in this grant application will be as follows: 1). Determine the functional significance of down-regulation of bc1-2 and cells survival pathway in cx43 mediated apoptosis and tumor suppression. 2). Determine the cx43 domains responsible for the activation of cx43-mediated apoptosis and tumor suppression. The cell lines expressing different domains of cx43 will be established by stable transfection and their function in relation to the activation of apoptosis and suppression of tumor cell growth will be determined. 3). Identification and characterization of the genes specifically activated or inactivated in cx43-transfected cells by cDNA array and differential display. Determine the functional significance of gene expressions identified with respect to the activation of apoptosis and suppression of tumor cell growth. 4). Determine if nuclear localization or cytoplasm localization is required to reverse the transformed phenotype to a """"""""normal"""""""" phenotype using cell proliferation assay, soft agar assay and tumorigenicity assay and enhance apoptosis under low serum condition. The results from these studies will enhance our understanding of the molecular mechanism of cx43 in the suppression of human glioblastoma cell growth. The elucidation of cx43 function involved in the tumor suppression with respect to activation of apoptosis eventually will provide a molecular basis for the development of anti-cancer compounds.
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