Stabilization of p73 by Nuclear IκB Kinase-α Mediates Cisplatin-induced Apoptosis

• Published in: The Journal of biological chemistry 2007-06, Vol.282 (25), p.18365
• Main Authors: Kazushige Furuya, Toshinori Ozaki, Takayuki Hanamoto, Mitsuchika Hosoda, Syunji Hayashi, Philip A. Barker, Kunio Takano, Masahiko Matsumoto, Akira Nakagawara
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M610522200

In response to DNA damage, p53 and its homolog p73 have a function antagonistic to NF-κB in deciding cell fate. Here, we show for the first time that p73, but not p53, is stabilized by physical interaction with nuclear IκB kinase (IKK)-α to enhance cisplatin (CDDP)-induced apoptosis. CDDP caused a significant increase in the amounts of nuclear IKK-α and p73α in human osteosarcoma-derived U2OS cells. Ectopic expression of IKK-α prolonged the half-life of p73 by inhibiting its ubiquitination and thereby enhancing its transactivation and pro-apoptotic activities. Consistent with these results, small interfering RNA-mediated knockdown of endogenous IKK-α inhibited the CDDP-mediated accumulation of p73α. The kinase-deficient mutant form of IKK-α interacted with p73α, but failed to stabilize it. Furthermore, CDDP-mediated accumulation of endogenous p73α was not detected in mouse embryonic fibroblasts (MEFs) prepared from IKK-α-deficient mice, and CDDP sensitivity was significantly decreased in IKK-α-deficient MEFs compared with wild-type MEFs. Thus, our results strongly suggest that the nuclear IKK-α-mediated accumulation of p73α is one of the novel molecular mechanisms to induce apoptotic cell death in response to CDDP, which may be particularly important in killing tumor cells with p53 mutation.