p19ARF-induced p53-independent apoptosis largely occurs through BAX |
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Authors: | Suzuki Hiroaki Kurita Megumi Mizumoto Kiyohisa Nishimoto Ikuo Ogata Etsuro Matsuoka Masaaki |
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Institution: | Department of Pharmacology, KEIO University School of Medicine, 35 Shinanomachi, Shinjuku-ku, 160-8582, Tokyo, Japan. |
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Abstract: | Combined disruption of the ARF gene and the p53 gene causes mouse predisposition to tumors of a wider variety and at a higher frequency than disruption of the p53 gene, indicating that the ARF gene has p53-independent anti-tumor function in addition to p53-dependent function. Coincidentally with this notion, ectopic expression of the p19(ARF) induces apoptosis for wild-type mouse embryo fibroblasts which have been immortalized by introduction of the SV40 virus genome (SV40-MEFs). The protein expression levels of p53, p21(Cip1), and Bax were not upregulated by ectopic expression of p19(ARF) in SV40-MEFs, indicating that expression of p19(ARF) induced apoptosis through p53-independent pathways in this system. Ectopic expression of p19(ARF) induced prominent apoptosis even in SV40-Bak-/-MEFs. In contrast, expression of p19(ARF) induced only a very low grade of apoptosis in Bax-/- or Bax-/-/Bak-/-SV40-MEFs. Remarkable attenuation of p19(ARF)-induced apoptosis by disruption of the Bax gene thus leads to the conclusion that Bax plays a major role in p53-independent apoptosis induced by p19(ARF). |
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Keywords: | The ARF tumor suppressor p53 Apoptosis Bax Cell cycle arrest |
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