Identification of novel p53-target genes and their physiological roles in tumor suppression and cellular senescence.

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p53 gene is frequently mutated in multiple cancer tissues and its gene product plays a pivotal role in tumor suppression. Although a number of p53 targets have been reported so far, the physiological functions of these genes in p53-dependent tumor suppression are still largely unknown. It was recently recognized that p53 was also implicated in the course of cellular senescence. To elucidate a variety of p53 functions, we have been screening and characterizing p53-target genes. Our previous cDNA microarray analysis revealed that more than 100 genes were up-regulated or down-regulated by exogenous introduction of p53. Here we report a total of 70 novel p53-target genes that were induced by ectopic expression of p53. Moreover, among 30 of such genes, we identified p53-binding sites on their genome sequences on which p53 protein could bind and regulate their transcription. To further clarify the physiological functions of these p53 targets, the expressions of those genes were analyzed in more than 1000 of cancer tissues using gene expression database that was constructed by means of cDNA microarray system established in our laboratory. We have identified two novel target genes that were significantly down-regulated in cancer tissues. One suppressed cell growth and the other suppressed cell migration by exogenous introduction to cancer cell lines. In addition, we examined the expression of p53 target genes during cellular senescence using normal human dermal fibroblast cells. We identified 6 genes that were up-regulated in senescent fibroblast cells and introduction of one of them into cells significantly inhibited cell growth and increased the proportion of senescence cells measured by β-gal staining. In our analysis, we have identified subset of p53-target genes which play an important role in tumor suppression or senescence induction that were mediated by p53.