As a transcription factor, p53 exerts a tumor suppressor activity by regulating a diverse array of genes involved in the control of cell cycle, apoptosis, differentiation, and DNA repair. Since the last competitive review of this project, we have identified seven novel p53 target genes. For example, we have found that MCGIO can induce cell cycle arrest and apoptosis and TAP1 may mediate tumor surveillance. We have also found that p2lB, a variant of p2l WAF1, is expressed in the Golgi apparatus and can induce apoptosis. These results have led us to hypothesize that multiple, parallel cell cycle control and apoptotic pathways are involved in p53 tumor suppression. To explore these further, we propose: (1) To identify additional novel p53 target genes. We will use the Affymetrix GeneChip assay to identify additional p53 target genes involved in the control of the cell cycle and apoptosis. We will analyze patterns of gene expression in response to various levels of p53 activation. Furthermore, we will determine whether one or more p53 response elements are present in the promoter or introns of the induced genes, and whether p53 regulates, or binds to, the potential response element(s). (2) To determine the mechanism by which wild type p53 and various mutants differentially regulate gene expression. (3) To determine the role of p2lB and MCG1O in p53 tumor suppression. We will analyze the role of p21B in p53-dependent apoptosis by somatic gene targeting and the mechanism by which p21 B induces apoptosis from within the Golgi. We will also determine the role of MCG1O in p53 tumor suppression, the mechanism by which MCG1O regulates gene expression, and whether MCG10 mediates activation or repression of some p53 target genes.
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