Abstract
The complex sequence of events leading to apoptotic cell death is governed by an elaborate regulatory scheme involving the actions of both initiator and executioner proteases. Among the most intensively studied of the initiator caspases is caspase-9, an essential throughput element in the so-called intrinsic or mitochondrially gated pathway of apoptosis. Previous reviews have described the proteolytic processing and activation of this protease in much detail; here we provide an update on caspase-9 regulation. A comprehensive description of the intra- and intermolecular events involved in modulating protein expression and activity are presented. Particular emphasis is placed on the role alternative splicing plays in the expression of functionally divergent protein isoforms, as well as, the participation of specific post-translational events in regulating caspase-9 activity. Such discrete modulation in reported activity characterizes, not only the pivotal role of this protease in the final commitment process itself, but also emphasizes the more general interplay that exists between mutually opposing cytotoxic and cytoprotective influences in maintaining cellular homeostasis.
Similar content being viewed by others
References
Hannun YA. Apoptosis and the dilemma of cancer chemotherapy. Blood 1997; 89: 1845–1853.
Martin SJ, Green DR. Protease activation during apoptosis: Death by a thousand cuts? Cell 1995; 82: 349–352.
Widmann C, Gibson S, Johnson GL. Caspase-dependent cleavage of signaling proteins during apoptosis. A turn-off mechanism for anti-apoptotic signals. J Biol Chem 1998; 273: 7141–7147.
Kuida K, Haydar TF, Kuan CY, et al. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 1998; 94: 325–337.
Hakem R, Hakem A, Duncan GS, et al. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 1998; 94: 339–352.
Krajewski S, Krajewska M, Ellerby LM, et al. Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc Natl Acad Sci USA 1999; 96: 5752–5757.
Susin SA, Lorenzo HK, Zamzami N, et al. Mitochondrial release of caspase-2 and-9 during the apoptotic process. J Exp Med 1999; 189: 381–394.
Shimohama S, Tanino H, Fujimoto S. Differential subcellular localization of caspase family proteins in the adult rat brain. Neurosci Lett 2001; 315: 125–128.
Ritter PM, Marti A, Blanc C, et al. Nuclear localization of procaspase-9 and processing by a caspase-3-like activity in mammary epithelial cells. Eur J Cell Biol 2000; 79: 358–364.
Boise LH, Gonzalez-Garcia M, Postema CE, et al. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 1993; 74: 597–608.
Shaham S, Horvitz HR. An alternatively spliced C. elegans ced-4 RNA encodes a novel cell death inhibitor. Cell 1996; 86: 201–208.
Droin N, Beauchemin M, Solary E, Bertrand R. Identification of a caspase-2 isoform that behaves as an endogenous inhibitor of the caspase cascade. Cancer Res 2000; 60: 7039–7047.
Seol DW, Billiar TR. A caspase-9 variant missing the catalytic site is an endogenous inhibitor of apoptosis. J Biol Chem 1999; 274: 2072–2076.
Srinivasula SM, Ahmad M, Guo Y, et al. Identification of an endogenous dominant-negative short isoform of caspase-9 that can regulate apoptosis. Cancer Res 1999; 59: 999–1002.
Angelastro JM, Moon NY, Liu DX, Yang A, Greene LA, Franke TF. Characterization of a novel isoform of caspase-9 that inhibits apoptosis. J Biol Chem 2001; 276: 12190–12200.
Fujita E, Jinbo A, Matuzaki H, Konishi H, Kikkawa U, Momoi T. Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9. Biochem Biophys Res Commun 1999; 264: 550–555.
Chalfant CE, Rathman K, Pinkerman RL, et al. De novo ceramide regulates the alternative splicing of caspase 9 and Bcl-x in A549 lung adenocarcinoma cells. Dependence on protein phosphatase-1. J Biol Chem 2002; 277: 12587–12595.
Stephanou A, Scarabelli TM, Knight RA, Latchman DS. Antiapoptotic activity of the free caspase recruitment domain of procaspase-9: A novel endogenous rescue pathway in cell death. J Biol Chem 2002; 277: 13693–13699.
Cardone MH, Roy N, Stennicke HR, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998; 282: 1318–1321.
Allan LA, Morrice N, Brady S, Magee G, Pathak S, Clarke PR. Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nat Cell Biol 2003; 5: 647–654.
Favata MF, Horiuchi KY, Manos EJ, et al. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 1998; 273: 18623–18632.
Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci USA 1995; 92: 7686–7689.
Terenzi F, Diaz-Guerra MJ, Casado M, Hortelano S, Leoni S, Bosca L. Bacterial lipopeptides induce nitric oxide synthase and promote apoptosis through nitric oxide-independent pathways in rat macrophages. J Biol Chem 1995; 270: 6017–6021.
Mannick JB, Miao XQ, Stamler JS. Nitric oxide inhibits Fas-induced apoptosis. J Biol Chem 1997; 272: 24125–24128.
Kim YM, Talanian RV, Billiar TR. Nitric oxide inhibits apoptosis by preventing increases in caspase-3-like activity via two distinct mechanisms.J Biol Chem 1997; 272: 31138–31148.
Mannick JB, Asano K, Izumi K, Kieff E, Stamler JS. Nitric oxide produced by human B lymphocytes inhibits apoptosis and Epstein-Barr virus reactivation. Cell 1994; 79: 1137–1146.
Genaro AM, Hortelano S, Alvarez A, Martinez C, Bosca L. Splenic B lymphocyte programmed cell death is prevented by nitric oxide release through mechanisms involving sustained Bcl-2 levels. J Clin Invest 1995; 95: 1884–1890.
Beauvais F, Michel L, Dubertret L. The nitric oxide donors, azide and hydroxylamine, inhibit the programmed cell death of cytokine-deprived human eosinophils. FEBS Lett 1995; 361: 229–232.
Chun SY, Eisenhauer KM, Kubo M, Hsueh AJ. Interleukin-1 beta suppresses apoptosis in rat ovarian follicles by increasing nitric oxide production. Endocrinology 1995; 136: 3120–3127.
ChengW, Li B, Kajstura J, et al. Stretch-induced programmed myocyte cell death. J Clin Invest 1995; 96: 2247–2259.
Dimmeler S, Haendeler J, Nehls M, Zeiher AM. Suppression of apoptosis by nitric oxide via inhibition of interleukin-1beta converting enzyme (ICE)-like and cysteine protease protein (CPP)-32-like proteases. J Exp Med 1997; 185: 601–607
Li J, Billiar TR, Talanian RV, Kim YM. Nitric oxide reversibly inhibits seven members of the caspase family via S-nitrosylation. Biochem Biophys Res Commun 1997; 240: 419–424.
Tenneti L, D’Emilia DM, Lipton SA. Suppression of neuronal apoptosis by S-nitrosylation of caspases. Neurosci Lett 1997; 236: 139–142.
Rossig L, Fichtlscherer B, Breitschopf K, et al. Nitric oxide inhibits caspase-3 by S-nitrosation in vivo. J Biol Chem 1999; 274: 6823–6826.
Mannick JB, Hausladen A, Liu L, et al. Fas-induced caspase denitrosylation. Science 1999; 284: 651–654.
Torok NJ, Higuchi H, Bronk S, Gores GJ. Nitric oxide inhibits apoptosis downstream of cytochrome C release by nitrosylating caspase 9. Cancer Res 2002; 62: 1648–1653.
Zeigler MM, Doseff AI, Galloway MF, et al. Presentation of nitric oxide regulates monocyte survival through effects on caspase-9 and caspase-3 activation. J Biol Chem 2003; 278: 12894–12902.
Mannick JB, Schonhoff C, Papeta N, et al. S-nitrosylation of mitochondrial caspases. J Cell Biol 2001; 154: 1111–1116.
Dimmeler S, Zeiher AM. Nitric oxide and apoptosis: Another paradigm for the double-edged role of nitric oxide. Nitric Oxide 1997; 1: 275–281.