title: Stabilization of p73 by nuclear IkappaB kinase-alpha mediates cisplatin-induced apoptosis.
abstract: In response to DNA damage, p53 and its homolog p73 have a function antagonistic to NF-kappaB in deciding cell fate. Here, we show for the first time that p73, but not p53, is stabilized by physical interaction with nuclear IkappaB kinase (IKK)-alpha to enhance cisplatin (CDDP)-induced apoptosis. CDDP caused a significant increase in the amounts of nuclear IKK-alpha and p73alpha in human osteosarcoma-derived U2OS cells. Ectopic expression of IKK-alpha 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-alpha inhibited the CDDP-mediated accumulation of p73alpha. The kinase-deficient mutant form of IKK-alpha interacted with p73alpha, but failed to stabilize it. Furthermore, CDDP-mediated accumulation of endogenous p73alpha was not detected in mouse embryonic fibroblasts (MEFs) prepared from IKK-alpha-deficient mice, and CDDP sensitivity was significantly decreased in IKK-alpha-deficient MEFs compared with wild-type MEFs. Thus, our results strongly suggest that the nuclear IKK-alpha-mediated accumulation of p73alpha 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.
authors: Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan; Second Department of Surgery, Yamanashi University School of Medicine, Yamanashi 409-3898, Japan.
authors: Kazushige
authors: K
authors: Furuya
authors: Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
authors: Toshinori
authors: T
authors: Ozaki
authors: Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
authors: Takayuki
authors: T
authors: Hanamoto
authors: Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
authors: Mitsuchika
authors: M
authors: Hosoda
authors: Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
authors: Syunji
authors: S
authors: Hayashi
authors: Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors: Philip A
authors: PA
authors: Barker
authors: Second Department of Surgery, Yamanashi University School of Medicine, Yamanashi 409-3898, Japan.
authors: Kunio
authors: K
authors: Takano
authors: Second Department of Surgery, Yamanashi University School of Medicine, Yamanashi 409-3898, Japan.
authors: Masahiko
authors: M
authors: Matsumoto
authors: Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan. Electronic address: akiranak@chiba-cc.jp.
authors: Akira
authors: A
authors: Nakagawara
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D019556:COS Cells; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D002945:Cisplatin / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051550:I-kappa B Kinase; D002945:Cisplatin