title: Noxa induces apoptosis in oncogene-expressing cells through catch-and-release mechanism operating between Puma and Mcl-1.
abstract: Tumor suppressor p53 induces apoptosis by transcriptional induction of Noxa and Puma, which encode the proapoptotic BH3-only member of the Bcl-2 family proteins. In the p53-mediated tumor surveillance system, p53 induces apoptosis or replicative senescence in oncogene-expressing cells, resulting in elimination of such cells. In this context, we previously found that Noxa and Puma synergistically induce apoptosis. Here, we found the adenovirus oncogene E1A to induce p53-dependently expression of Puma, but not Noxa. The induced Puma associates with antiapoptotic Bcl-2 protein Mcl-1, accompanied by accumulated Mcl-1 protein on mitochondria. Moreover, E1A also reduces expression of the antiapoptotic Bcl-2 protein Bcl-X(L). In contrast, the DNA-damaging agent adriamycin induces Noxa expression in E1A-expressing cells. Interestingly, Mcl-1 knockdown itself induced apoptosis in E1A-expressing MEFs. Furthermore, Noxa displaced Puma's association with Mcl-1, accompanied by Mcl-1 degradation and apoptosis induction by activating mitochondrial apoptotic executers Bax and Bak. These results suggest that p53-induced apoptosis in oncogene-expressing cells is regulated by differential induction and sequential activation of Noxa and Puma. Accumulated Puma by oncogene enhances susceptibility to apoptosis through "catch" in mitochondria by Mcl-1. Subsequently, in response to DNA-damage, Noxa efficiently induces apoptosis by "release" of Puma from Mcl-1.
authors.affiliation: Department of Molecular Oncology, Institute of Gerontology, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki 211-8533, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nakajima
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tanaka
mesh_terms: D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D004249:DNA Damage; D055785:Gene Knockdown Techniques; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009857:Oncogenes; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D017500:Adenovirus E1A Proteins; D051017:Apoptosis Regulatory Proteins; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C488588:PUMA protein, mouse; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein