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In response to DNA damage, p53 tumor suppressor gene plays central roles in cell fate determination, including cell cycle arrest, DNA repair, senescence and apoptosis. Although this cell fate determination is believed to be achieved by the ability of p53 to coordinate transcription of its target genes, mechanisms underlying these processes are still uncertain. Therefore, we attempted to integrate functional contributions of p53 family proteins to this mechanism and found that coordinated but distinct regulation of p53 and p53 family proteins are crucial for the mechanism. Under weak DNA damaging stimuli, p53 alone is stabilized in rapid kinetics. This p53 by itself is only sufficient for transactivating non-apoptotic genes (WAF1, MDM2, cyclin G, GADD45 and p53R2), but inefficient for apoptosis inducing genes (BAX, PUMA, NOXA and p53AIP1), thereby induces growth arrest and senescence. When DNA damage is beyond the threshold, p53 family proteins are stabilized in delayed kinetics by a mechanism distinct from that of p53 achieved mainly through MDM2 pathway. Strong DNA damage evokes translocation of IKKγ, a regulatory subunit of IKK signalosome indispensable for NF-κB activation, to the nucleus at γ-H2AX foci, landmarks for DNA double strand breaks. This nuclear IKKγ inhibit p51 ubiquitin ligase (p51UBL) activity, thereby protecting p53 family proteins from proteasomal breakdown. We newly identified this p51UBL, an E3 ubiquitin ligase specific to TAp51/p63 and TAp73, also known as a protein encoded by a gene causing split hand and mal foot syndrome (SHFM3/dactylin) in addition to Itch. Since this regulation takes place in delayed kinetics, it also allows damaged cells to accumulate both p53 and p53 family proteins in delayed kinetics. By conducting series of experiments, we found that the formation of either p53/p73 or p53/p51 hetero-oligomer is likely to be prerequisite for transactivation of proapoptotic genes. Thus, this delayed induction of p73 and/or p51, in cooperation with sustained activation of p53 induces cellular apoptosis. We also speculate that IKKγ may sense the degree of the DNA damage and determine cell fate by switching either p53 family protein or NF-κB signaling pathway.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA