ROLE OF THE P34CDC2 RELATED PITSLRE PROTEIN KINASES

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Recurring alterations of chromosome 1 represent the most frequent site of structural chromosome abnormalities across all human solid tumors, including human cutaneous malignant melanoma. In melanoma, breakpoints involving chromosome 1 often accumulate at 1p36.3. The two genes (Cdc2L1 and Cdc2L2) encoding cyclin dependent kinase 11 proteins (CDK11, formerly known as PITSLRE) are localized to chromosome band region 1p36. Several lines of evidence indicate that CDK11 is involved in apoptotic signal transduction. We have demonstrated deletion of Cdc2L alleles in melanoma. We can also show that the CDK11p11¿ isoform is cleaved by caspase 3 into a smaller 60kDa (CDK11p6¿) fragment that translocates to mitochondria and a 46kDa isoform (CDK11^6) that retains kinase activity and associates with eukaryotic initiation factor^ f subunit (elF3f). Our preliminary studies indicate that: 1) CDK11p6¿ translocates to mitochondria and is associated with a disruption of mitochondrial membrane potential; 2) the association of CDK11p46 with elFSf is associated with ribosomal RNA degradation; 3) Both CDK11 and elFSf expression are reduced in melanomas as well as other cancers. Hence, the principal hypothesis to be tested is that CDK11 is pro-apoptotic acting at two distinct levels within the cell (in mitochondria and in the nucleus) and that haplo-insufficiency of Cdc2L, encoding CDK11, disrupts apoptosis and contributes to melanoma. To address this hypothesis the following specific aims will be pursued: Aim 1: To determine the mechanism by which CDK11p6¿ compromises mitochondrial function. Aim 2: To elucidate how CDK11p46 phosphorylation of elFSf contributes to apoptosis. Aim 3: To determine if alterations occur in the CDK11/elF3f pathway in melanoma progression. Aim 4: To determine if haplo-insufficiency of Cdc2L makes mice more prone to tumor development. There is an increased awareness that apoptotic cell death is a key factor restraining tumor development and that dysfunctional apoptosis is a common feature of cancer cells. This is particularly true for melanoma, which is generally resistant to apoptosis induced by radiation and chemotherapeutic drugs, accounting for its poor prognosis. The data expected from these studies will provide novel insights into the mechanism involved in cell proliferation and apoptosis in melanoma. The greatest impact will be realized in the provision of novel molecular targets for therapeutic intervention strategies.