Synergistic induction of apoptosis by p53-inducible Bcl-2 family proteins Noxa and Puma.
One critical tumor-suppressive function of p53 is the induction of apoptosis in oncogene-expressing cells. In this context, p53-inducible genes encoding the BH3-only proteins of the Bcl-2 family, Noxa and Puma, were identified. Gene knockout studies revealed that both Noxa and Puma are involved in apoptosis induction in oncogene-expressing cells. BH3-only proteins induce apoptosis, and activate the downstream apoptosis effectors Bax and Bak. In this study, we found that Noxa and Puma synergistically activate Bax and Bak, and induce apoptosis. Although Noxa activates Bak by inactivating Mcl-1 and Bcl-X(L), gene knockdown studies revealed that neither Mcl-1 nor Bcl-X(L) is involved in this synergism. Moreover, Puma, but not Noxa, directly activated Bax in the absence of Bak, and Noxa enhanced Puma-mediated Bax activation in Bak-deficient cells. These results suggest the existence of a novel regulatory pathway for Noxa-mediated apoptosis. Although we detected synergistic induction of apoptosis by Noxa and Bim, a tumor suppressive transcriptional factor FoxO3-inducible protein, no such synergism was observed for other pairs of BH3-only proteins, Bim and Bid, or Bim and Puma. From these results, it can be considered that p53 carefully controls apoptosis by allowing two molecules to share full ability to induce apoptosis.
Nakajima
Wataru
W
Department of Molecular Oncology, Institute of Gerontology, Graduate School of Medicine, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki, Kanagawa 211-8533, Japan.
Tanaka
Nobuyuki
N
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008928:Mitochondria; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C579094:Mcl1 protein, mouse; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein