Nitric Oxide Suppression of Apoptosis Occurs in Association with an Inhibition of Bcl-2 Cleavage and Cytochrome cRelease*

It is now known that caspase-3-like protease activation can promote Bcl-2 cleavage and mitochondrial cytochromec release and that these events can lead to further downstream caspase activation. NO has been proposed as a potent, endogenous inhibitor of caspase-3-like protease activity. Experiments were carried out to determine whether NO could interrupt Bcl-2 cleavage or cytochrome c release by the inhibition of caspase activity linking these events. NO inhibited the capacity of purified caspase-3 to cleave recombinant Bcl-2. Both Bcl-2 cleavage and cytochrome c release were inhibited in tumor necrosis factor α- and actinomycin d-treated MCF-7 cells exposed to NO donors. The NO-mediated inhibition of Bcl-2 cleavage and cytochrome c release occurred in association with an inhibition of apoptosis and caspase-3-like activation. Thus, NO suppresses a key step in the positive feedback amplification of apoptotic signaling by preventing Bcl-2 cleavage and cytochromec release.

[1]  K. Johal,et al.  INHIBITION OF APOPTOSIS BY NITRIC OXIDE DONORS IN GUINEA-PIG GASTRIC MUCOUS CELLS , 1999 .

[2]  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.

[3]  G. Kroemer,et al.  The Permeability Transition Pore Complex: A Target for Apoptosis Regulation by Caspases and Bcl-2–related Proteins , 1998, The Journal of experimental medicine.

[4]  Alan G. Porter,et al.  Caspase-3 Is Required for DNA Fragmentation and Morphological Changes Associated with Apoptosis* , 1998, The Journal of Biological Chemistry.

[5]  J. Farber,et al.  The Overexpression of Bax Produces Cell Death upon Induction of the Mitochondrial Permeability Transition* , 1998, The Journal of Biological Chemistry.

[6]  C. Borner,et al.  Alphaviruses induce apoptosis in Bcl‐2‐overexpressing cells: evidence for a caspase‐mediated, proteolytic inactivation of Bcl‐2 , 1998, The EMBO journal.

[7]  D G Kirsch,et al.  Modulation of cell death by Bcl-XL through caspase interaction. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[8]  S. Nagata,et al.  Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis , 1998, Nature.

[9]  S. Nagata,et al.  A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD , 1998, Nature.

[10]  E. Cheng,et al.  Conversion of Bcl-2 to a Bax-like death effector by caspases. , 1997, Science.

[11]  T. Billiar,et al.  Nitric Oxide Inhibits Apoptosis by Preventing Increases in Caspase-3-like Activity via Two Distinct Mechanisms* , 1997, The Journal of Biological Chemistry.

[12]  T. Billiar,et al.  Nitric oxide reversibly inhibits seven members of the caspase family via S-nitrosylation. , 1997, Biochemical and biophysical research communications.

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

[14]  G Waksman,et al.  Comparison of the ion channel characteristics of proapoptotic BAX and antiapoptotic BCL-2. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[15]  J. Stamler,et al.  Nitric Oxide Inhibits Fas-induced Apoptosis* , 1997, The Journal of Biological Chemistry.

[16]  M. Boese,et al.  Inhibition of Glutathione Reductase by Dinitrosyl-Iron-Dithiolate Complex* , 1997, The Journal of Biological Chemistry.

[17]  F Gambale,et al.  Inhibition of Bax channel-forming activity by Bcl-2. , 1997, Science.

[18]  Simon C Watkins,et al.  Targeting nitric oxide (NO) delivery in vivo. Design of a liver-selective NO donor prodrug that blocks tumor necrosis factor-alpha-induced apoptosis and toxicity in the liver. , 1997, Journal of medicinal chemistry.

[19]  J C Reed,et al.  Channel formation by antiapoptotic protein Bcl-2. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Xiaodong Wang,et al.  DFF, a Heterodimeric Protein That Functions Downstream of Caspase-3 to Trigger DNA Fragmentation during Apoptosis , 1997, Cell.

[21]  J. Mankovich,et al.  Substrate Specificities of Caspase Family Proteases* , 1997, The Journal of Biological Chemistry.

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

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

[24]  M. Nehls,et al.  Suppression of Apoptosis by Nitric Oxide via Inhibition of Interleukin-1β–converting Enzyme (ICE)-like and Cysteine Protease Protein (CPP)-32–like Proteases , 1997, The Journal of experimental medicine.

[25]  Simon C Watkins,et al.  Nitric Oxide Protects Cultured Rat Hepatocytes from Tumor Necrosis Factor-α-induced Apoptosis by Inducing Heat Shock Protein 70 Expression* , 1997, The Journal of Biological Chemistry.

[26]  G. Kroemer,et al.  Bcl-2 inhibits the mitochondrial release of an apoptogenic protease , 1996, The Journal of experimental medicine.

[27]  David Wallach,et al.  Involvement of MACH, a Novel MORT1/FADD-Interacting Protease, in Fas/APO-1- and TNF Receptor–Induced Cell Death , 1996, Cell.

[28]  Matthias Mann,et al.  FLICE, A Novel FADD-Homologous ICE/CED-3–like Protease, Is Recruited to the CD95 (Fas/APO-1) Death-Inducing Signaling Complex , 1996, Cell.

[29]  S. Nagata,et al.  Sequential activation of ICE-like and CPP32-like proteases during Fas-mediated apoptosis , 1996, Nature.

[30]  M. Leist,et al.  Tumor necrosis factor-induced hepatocyte apoptosis precedes liver failure in experimental murine shock models. , 1995, The American journal of pathology.

[31]  C. Martínez-A,et al.  Splenic B lymphocyte programmed cell death is prevented by nitric oxide release through mechanisms involving sustained Bcl-2 levels. , 1995, The Journal of clinical investigation.

[32]  J. Lancaster,et al.  Loss and Degradation of Enzyme-bound Heme Induced by Cellular Nitric Oxide Synthesis (*) , 1995, The Journal of Biological Chemistry.

[33]  J. Stamler,et al.  Nitric oxide produced by human B lymphocytes inhibits apoptosis and Epstein-Barr virus reactivation , 1994, Cell.

[34]  S. Tannenbaum,et al.  Nitrosation of amines by stimulated macrophages. , 1987, Carcinogenesis.

[35]  D. Green,et al.  Mitochondrial cytochrome c release in apoptosis occurs upstream of DEVD‐specific caspase activation and independently of mitochondrial transmembrane depolarization , 1998, The EMBO journal.

[36]  J. Beckman,et al.  Reactions between nitric oxide, superoxide, and peroxynitrite: footprints of peroxynitrite in vivo. , 1995, Advances in pharmacology.