Oncogene-dependent apoptosis is mediated by caspase-9.

Understanding how oncogenic transformation sensitizes cells to apoptosis may provide a strategy to kill tumor cells selectively. We previously developed a cell-free system that recapitulates oncogene dependent apoptosis as reflected by activation of caspases, the core of the apoptotic machinery. Here, we show that this activation requires a previously identified apoptosis-promoting complex consisting of caspase-9, APAF-1, and cytochrome c. As predicted by the in vitro system, preventing caspase-9 activation blocked drug-induced apoptosis in cells sensitized by E1A, an adenoviral oncogene. Oncogenes, such as E1A, appear to facilitate caspase-9 activation by several mechanisms, including the control of cytochrome c release from the mitochondria.

[1]  Yuri Lazebnik,et al.  Multiple species of CPP32 and Mch2 are the major active caspases present in apoptotic cells , 1997, The EMBO journal.

[2]  Dean P. Jones,et al.  Prevention of Apoptosis by Bcl-2: Release of Cytochrome c from Mitochondria Blocked , 1997, Science.

[3]  D. Goeddel,et al.  FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. , 1998, Science.

[4]  G. Evan,et al.  Requirement for the CD95 receptor-ligand pathway in c-Myc-induced apoptosis. , 1997, Science.

[5]  S. Korsmeyer,et al.  The adenovirus E1A proteins induce apoptosis, which is inhibited by the E1B 19-kDa and Bcl-2 proteins. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Junying Yuan,et al.  Human ICE/CED-3 Protease Nomenclature , 1996, Cell.

[7]  J C Reed,et al.  Bax directly induces release of cytochrome c from isolated mitochondria. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[8]  G. Evan,et al.  Oncogenes and cell death. , 1994, Current opinion in genetics & development.

[9]  E. White Regulation of Apoptosis by the Transforming Genes of the DNA Tumor Virus Adenovirus , 1993, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[10]  M. Peter,et al.  FLICE Is Predominantly Expressed as Two Functionally Active Isoforms, Caspase-8/a and Caspase-8/b* , 1997, The Journal of Biological Chemistry.

[11]  Y. Lazebnik,et al.  Oncogene-dependent apoptosis in extracts from drug-resistant cells. , 1997, Genes & development.

[12]  D. Green,et al.  The Release of Cytochrome c from Mitochondria: A Primary Site for Bcl-2 Regulation of Apoptosis , 1997, Science.

[13]  S. Lowe,et al.  Selective induction of p53 and chemosensitivity in RB-deficient cells by E1A mutants unable to bind the RB-related proteins. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[14]  S. Srinivasula,et al.  Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade , 1997, Cell.

[15]  T. Kuwana,et al.  Apoptosis Induction by Caspase-8 Is Amplified through the Mitochondrial Release of Cytochrome c * , 1998, The Journal of Biological Chemistry.

[16]  F. Graham,et al.  Characteristics of a human cell line transformed by DNA from human adenovirus type 5. , 1977, The Journal of general virology.

[17]  S. Korsmeyer,et al.  Bax suppresses tumorigenesis and stimulates apoptosis in vivo , 1997, Nature.

[18]  V. Dixit,et al.  Caspase-9, Bcl-XL, and Apaf-1 Form a Ternary Complex* , 1998, The Journal of Biological Chemistry.

[19]  S. Korsmeyer,et al.  bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[20]  V. Cryns,et al.  Proteases to die for. , 1998, Genes & development.

[21]  C. Borner,et al.  Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c , 1998, Nature.