The tumor suppressor gene INK4A (MTS1, CDK41, CDKN2) codes for p16, an inhibitor of the G1 cyclin-dependent kinases CDK4 and CDK6. Deletion or inactivation of this gene is a frequent event in the oncogenic process. P16 is expressed at very low levels in most normal cells, including lymphoid cells and their precursors, but it is up-regulated by unknown mechanisms before senescence. The applicant proposes that p16 up-regulation partially mediates the irreversible cell cycle arrest of senescence, and that deletion or inactivation of INK4A allows progression of a neoplastic clone that has growth arrested at senescence. Inactivation of INK4A by gene deletion, point mutation, and DNA methylation has been reported in neoplastic cells. On the basis of the applicant's previous results, he postulates that in some neoplastic cells suppression of p16 expression can also be achieved by post-transcriptional down-regulation.
The specific aims of this project are: 1) To study the role of p16 in senescence and oncogenesis through expression of p16 from transfected expression vectors, and down-regulation of its expression by antisense strategies. 2) To study the mechanisms of p16 regulation in normal senescent cells and neoplastic cells. 3) To study the post-transcriptional down-regulation of p16 in leukemia and lymphoma cell lines. 4) To measure the prevalence of post-transcriptional down-regulation of INK4A in primary leukemias and lymphomas. During oncogenesis, cell immortalization is an essential step to achieve full malignant transformation. P16 participates in the control of cell senescence. Therefore, it is important to understand its role and transcriptional regulation in senescent and immortal cells. Since in some lymphoma and ALL cell lines INK4A expression is inhibited at a post-transcriptional level, it is important to determine if this phenomenon is relevant to oncogenesis in primary tumors. If the post-transcriptional down-regulation of p16 is relevant, we should try to understand its mechanism to explore the possibility of manipulating it for therapeutic purposes.
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