Inhibitor of Normal Growth (ING)

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Nutlin-3a, an inhibitor of murine double minute 2(MDM2), has the ability to activate p53, leading to p53-regulated processes such as apoptosis and cell growth arrest. We found that premature cellular senescence was a phenotype induced by Nutlin-3a-mediated activation of endogenouse p53 functions in normal human fibroblasts. The miR-34 families of microRNAs (miR-34a, miR-34b and miR-34c) were upregulated with the Nutlin-3a-induced senescence in a p53-dependent manner, suggesting the physiological importance of the endogenously expressed miR-34 family in the regulation of cellular senescence. Among the protein-coding genes which were altered in expression by Nutlin-3a, we selected ING2 for further study; a gene we studied previously. p53 directly bound to the ING2 gene promoter to transcriptionally repress it. The siRNA knockdown of ING2 induced cellular senescence as effectively as Nutlin-3a treatment in human fibroblasts. While the Nutlin-3a-induced senescence was p53-dependent, the ING2 knockdown caused senescence even in the abscence of p53, suggesting that ING2 is a downstream effector of Nutlin-3a-induced, p53-mediated signaling to cellular senescence. Two different facets of the functional interplay between p53 and ING2 in the regulation of senescence are suggested by our studies: (a) the enhanced activity of ING2 induces senescence by post-translationally activating p53; and (b) the endogenous levels of ING2 restricts senescence under non-stressed conditions without p53 activation.