Mechanisms underlying cell cycle regulation and induction of apoptosis by transcription factor p53.

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Mechanisms underlying Cell cycle regulation and induction of apoptosis by transcription factor p53 have been extensively studied in the context of tumor suppression. During our studies, we identified a novel gene Noxa, whose induction is dependent on. Noxa encodes a BH3-only member of the Bcl-2 family proteins and, when ectopically expressed, it induces apoptosis. We studied the role of Noxa in vitro and in vivo, by the gene-targeting approach. The mouse embryonic fibroblasts deficient in Noxa (Noxa^<-/-> MEFs) showed notable resistance to oncogene-dependent apoptosis in response to DNA damage. These MEFs also showed increased sensitivity to oncogene-induced cell transformation in vitro. Furthermore, Noxa^<-/-> mice showed resistance to gastrointestinal death following X-ray irradiation, accompanied with impaired apoptosis in the epithelial cells of small intestinal crypts, thereby indicating the role of Noxa in the p53 response in vivo. After we published these results, gene knockout studies of Noxa related BH3-only member PUMA was published. In this experiment, decreased oncogene-dependent in MEFs, and also loss of Puma protected lymphocytes from apoptosis. Therefore, BH3-only factors are critical mediators of the apoptotic responses induced by p53.