Executioners of apoptosis in pancreatic β-cells: Not just for cell death

American Journal of Physiology - Endocrinology and Metabolism

Volumn 298, Issue 4, 2010, Pages

  Choi, Diana ^a   Woo, Minna ^a,b  

^a ST MICHAEL'S HOSPITAL   (Canada)

^b ST MICHAEL'S HOSPITAL   (Canada)

Author keywords

Caspases; Diabetes

Indexed keywords

CASPASE; CASPASE 3; CASPASE 3 INHIBITOR; CASPASE 8; CASPASE INHIBITOR; PROTEIN BCL 2; SURVIVIN;

APOPTOSIS; CELL DEATH; CELL PROLIFERATION; HOMEOSTASIS; HUMAN; INSULIN DEPENDENT DIABETES MELLITUS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREAS ISLET BETA CELL; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; APOPTOSIS; APOPTOSIS REGULATORY PROTEINS; CELL DEATH; DIABETES MELLITUS, TYPE 1; DIABETES MELLITUS, TYPE 2; HOMEOSTASIS; HUMANS; INHIBITOR OF APOPTOSIS PROTEINS; INSULIN-SECRETING CELLS; MICE;

EID: 77949839261     PISSN: 01931849     EISSN: 15221555     Source Type: Journal    
DOI: 10.1152/ajpendo.00696.2009     Document Type: Review

References (99)

1. Adrain C, Martin SJ. Double knockout blow for caspases. Science 311: 785-786, 2006.
2. Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J. Human ICE/CED-3 protease nomenclature. Cell 18: 171, 1996.
3. Antonsson B, Conti F, Ciavatta A, Motessuit S, Lewis S, Martinou I, Bernasconi L, Bernard A, Mermod JJ, Mazzei G, Maundrell K, Gambale F, Sadoul R, Martinou JC. Inhibition of Bax channel-forming activity by Bcl-2. Science 277: 370-372, 1997.
4. Apostolou I, Hao Z, Rajewsky K, von Boehmer H. Effective destruction of Fas-deficient insulin-producing β-cells in Type 1 diabetes. J Exp Med 198: 1103-1106, 2003.
5. Beisner DR, Chen IL, Kolla RV, Hoffman A, Hedrick SM. Cutting edge innate immunity conferred by B cells is regulated by caspase 8. J Immunol 175: 3469-3473, 2005.
6. Bonner-Weir S. Life and death of the pancreatic beta cells. Trends Endocrinol Metab 11: 375-378, 2000.
7. Bonner-Weir S. Perspective: Postnatal pancreatic beta cell growth. Endocrinology 141: 1926-1929, 2000.
8. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52: 102-110, 2003.
9. Carlile GW, Smith DH, Wiedmann M. caspase-3 has a nonapoptotic function in erythroid maturation. Blood 103: 4310-4316, 2004.
10. Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94: 727-737, 1998.
11. Cerretti DP, Kozlosky CJ, Mosley B, Nelson N, Van Ness K, Greenstreet TA, March CJ, Kronheim SR, Druck T, Cannizzaro LA, Huebner K, Black RA. Molecular cloning of the interleukin-1β converting enzyme. Science 256: 97-100, 1992.
12. Cheng Y, Deshmukh M, D'Costa A, Demaro JA, Gidday JM, Shah A, Sun Y, Jacquin MF, Johnson EM, Holtzman DM. caspase inhibitor afford neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischemic brain injury. J Clin Invest 101: 1992-1999, 1998.
13. Chervonsky AV, Wang Y, Wong FS, Visintin I, Falvell RA, Janeway CA Jr, Matis LA. The role of Fas in autoimmune diabetes. Cell 89: 17-24, 1997.
14. Choi D, Radziszewska A, Schroer SA, Liadis N, Liu Y, Zhang Y, Lam PL, Sheu L, Hao Z, Gaisano HY, Woo M. Deletion of Fas in the pancreatic β-cells leads to enhanced insulin secretion. Am J Physiol Endocrinol Metab 297: E1304-E1312, 2009.
15. Cohen GM. caspases: the executioners of apoptosis. Biochem J 326: 1-16, 1997.
16. Degterev A, Boyce M, Yuan J. A decade of caspases. Oncogene 22: 8543-8567, 2003.
17. Desbarats J, Birge RB, Mimouni-Rongy M, Weinstein DC, Palerme JS, Newell MK. Fas engagement induces neurite growth through ERK activation and p35 upregulation. Nat Cell Biol 5: 118-125, 2003.
18. Desbarats J, Newell MK. Fas engagement accelerates liver regeneration after partial hepatectomy. Nat Med 6: 920-923, 2000.
19. Dohi T, Salz W, Costa M, Ariyan C, Basadonna GP, Altieri DC. Inhibition of apoptosis by survivin improves transplantation of pancreatic islets for treatment of diabetes in mice. EMBO Rep 7: 438-443, 2006.
20. Dyer MJ, Zani VJ, Lu WZ, O'Byrne A, Mould S, Chapman R, Heward JM, Kayano H, Jadayel D, Matutes E. BCL2 translocations in leukemia of mature B cells. Blood 83: 3682-3688, 1994.
21. Emamaullee JA, Davis J, Pawlick R, Toso C, Merani S, Cai SX, Tseng B, Shapiro AM. The caspase selective inhibitor EP1013 augments human islet graft function and longevity in marginal mass islet transplantation in mice. Diabetes 57: 1556-1566, 2008.
22. Emamaullee JA, Liston P, Korneluk RG, Shapiro AM, Elliott JF. XIAP overexpression in islet beta-cells enhances engraftment and minimizes hypoxia-reperfusion injury. Am J Transplant 5: 1297-1305, 2005.
23. Emamaullee JA, Rajotte RV, Liston P, Korneluk RG, Lakey JR, Shapiro AM, Elliott JF. XIAP overexpression in human islets prevents early posttransplant apoptosis and reduces the islet mass needed to treat diabetes. Diabetes 54: 2541-2548, 2005.
24. Emamaullee JA, Stanton L, Schur C, Shapiro AM. caspase inhibitor therapy enhances marginal mass islet graft survival and preserves longterm function in islet transplantation. Diabetes 56: 1289-1298, 2007.
25. Farber A, Connors J, Friedlander R, Wagner R, Powell R, Cronenwett J. A specific inhibitor of apoptosis decreases tissue injury after intestinal ischemia-reperfusion in mice. J Vasc Surg 30: 72-760, 1999.
26. Fernandes-Alnemri T, Litwack G, Alnemri ES. CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein ced-3 and mammalian interleukin-1β-converting enzyme. J Biol Chem 269: 30761-30764, 1994.
27. Fernando P, Kelly JR, Balazi K, Slack RS, Megeney LA. caspase-3 activity is required for skeletal muscle differentiation. Proc Natl Acad Sci USA 99: 11025-11030, 2002.
28. Finegood DT, Scaglia L, Bonner-Weir S. Dynamics of beta-cell mass in the growing rat pancreas Estimation with a simple mathematical model. Diabetes 44: 249-256, 1995.
29. Florez JC. Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes? Diabetologia 51: 110-1110, 2008.
30. Gunton JE, Kulkarni RN, Yim S, Okada T, Hawthorne WJ, Tseng YH, Roberson RS, Ricordi C, O'Connell PJ, Gonzalez FJ, Kahn CR. Loss of ARNT/HIF1beta mediates altered gene expression and pancreaticislet dysfunction in human type 2 diabetes. Cell 122: 337-349, 2005.
31. Harding HP, Ron D. Endoplasmic reticulum stress and development of diabetes: a review. Diabetes 51, Suppl 3: S455-S461, 2002.
32. Hengartner MO, Horvitz HC. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 76: 665-676, 1994.
33. Hirota N, Otabe S, Nakayama H, Yuan X, Yamada K. Sequential activation of caspases and synergistic beta-cell cytotoxicity by palmitate and anti-Fas antibodies. Life Sci 79: 1312-1316, 2006.
34. Huang DC, Strasser A. BH3-only proteins - essential initiators of apoptotic cell death. Cell 103: 839-842, 2000.
35. Huo J, Luo RH, Metz SA, Li G. Activation of caspase-2 mediates the apoptosis induced by GTP-depletion in insulin-secreting (HIT-T15) cells. Endocrinology 143: 1695-1704, 2002.
36. Ingrid H, Wilhelm D, Bohler T, Angel P, Debatin KM. Activation of CD95 (APO-1/Fas) signaling by ceramide mediates cancer therapy-induced apoptosis. EMBO J 16: 6200-6208, 1997.
37. Irawaty W, Kay TW, Thomas HE. Transmembrane TNF and IFNγ induce caspase-independent death of primary mouse pancreatic beta cells. Autoimmunity 35: 369-375, 2002.
38. Itoh N, Imagawa A, Hanafusa T, Waguri M, Yamamoto K, Iwahashi H, Moriwaki M, Nakajima H, Miyagawa J, Namba M, Makino S, Nagata S, Kono N, Matsuzawa Y. Requirement of Fas for the development of autoimmune diabetes in nonobese diabetic mice. J Exp Med 186: 613-618, 1997.
39. Iwata A, Harlan JM, Vedder NB, Winn RK. The caspase inhibitor z-VAD is more effective than CD18 adhesion blockade in reducing muscle ischemia-reperfusion injury: implication for clinical trials. Blood 100: 2077-2080, 2002.
40. Jacobson MD, Weil M, Raff MC. Programmed cell death in animal development. Cell 88: 347-354, 1997.
41. Jiang Y, Nishimura W, Devor-Henneman D, Kusewitt D, Wang H, Holloway MP, Dohi T, Sabo E, Robinson ML, Altieri DC, Sharma A, Altura RA. Postnatal expansion of the pancreatic beta-cell mass is dependent on survivin. Diabetes 57: 2718-2727, 2008.
42. Juo P, Kuo CJ, Yuan J, Blenis J. Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade. Curr Biol 8: 1001-1008, 1998.
43. Kang KH, Lee KH, Kim MY, Choi KH. caspase-3-mediated cleavage of the NF-kappa B subunit p65 at the NH2 terminus potentiates naphthoquinone analog-induced apoptosis. J Biol Chem 276: 24638-24644, 2001.
44. Kang TB, Ben-Moshe T, Varfolomeev EE, Pewzner-Jung Y, Yogev N, Jurewicz A, Waisman A, Brenner O, Haffner R, Gustafsson E, Ramakrishnan P, Lapidot T, Wallach D. caspase-8 serves both apoptotic and non-apoptotic roles. J Immunol 173: 2976-2984, 2004.
45. Kassem SA, Ariel I, Thornton PS, Scheimberg I, Glaser B. Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hypinsulinemia of infancy. Diabetes 49: 1325-1333, 2000.
46. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26: 239-257, 1972.
47. Kim H, Rafiuddin-Shah M, Tu HC, Jeffers JR, Zambetti GP, Hsieh JJ, Cheng EH. Hierarchical regulation of mitochondrion-dependent apoptosis by Bcl-2 subfamilies. Nat Cell Biol 8: 1348-1358, 2006.
48. Kischkel FC, Lawrence DA, Tinel A, LeBlanc H, Virmani A, Schow P, Gazdar A, Blenis J, Arnott D, Ashkenazi A. Death receptor recruitment of endogenous caspase-10 and apoptosis initiation in the absence of caspase-8. J Biol Chem 276: 46639-46646, 2001.
49. Kumar S. caspase function in programmed cell death. Cell Death Differ 14: 32-43, 2007.
50. Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R, Green DR, Newmeyer D. Bid, Bax, and lipids cooperate to form supremolecular openings in the outer mitochondrial membrane. Cell 111: 331-342, 2002.
51. Lakhani SA, Masud A, Kuida K, Porter GA Jr, Booth CJ, Mehal WZ, Inayat I, Flavell RA. caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science 311: 847-851, 2006.
52. Lavrik IN, Golks A, Baumann S, Krammer PH. caspase-2 is activated at the CD95 death-inducing signaling complex in the course of CD95-induced apoptosis. Blood 108: 559-565, 2006.
53. Laybutt DR, Preston AM, Akerfeldt MC, Kench JG, Busch AK, Biankin AV, Biden TJ. Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 50: 752-763, 2007.
54. Leonardi O, Mints G, Hussain MA. Beta-cell apoptosis in the pathogenesis of human type 2 diabetes mellitus. Eur J Endocrinol 149: 99-102, 2003.
55. Levkau B, Koyama H, Raines EW, Clurman BE, Herren B, Orth K, Roberts JM, Ross R. Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activations of Cdk2: role of a caspase cascade. Mol Cell 1: 553-563, 1998.
56. Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94: 491-501, 1998.
57. Liadis N, Murakami K, Eweida M, Elford AR, Sheu L, Gaisano HY, Hakem R, Ohashi PS, Woo M. Caspase-3-dependent beta-cell apoptosis in the initiation of autoimmune diabetes mellitus. Mol Cell Biol 25: 3620-3629, 2005.
58. Liadis N, Salmena L, Kwan E, Tajmir P, Schroer SA, Radziszewska A, Li X, Sheu L, Eweida Xu S, Gaisano HY, Hakem R, Woo M. Distinct in vivo roles of caspase-8 in β-cells in physiological and diabetes models. Diabetes 56: 2302-2311, 2007.
59. Like AA, Rossini AA. Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus. Science 193: 415-417, 1976.
60. Marchetti P, Del Prato S, Lupi R, Guerra SD. The pancreatic beta-cell in human type 2 diabetes. Nutr Metab Cardiovasc Dis 16, Suppl 1: S3-S6, 2006.
61. Mathis D, Vence L, Benoist C. β-Cell death during progression to diabetes. Nature 414: 792-798, 2001.
62. Marx J. Nobel Prize in Physiology or Medicine. Tiny worm takes a star turn. Science 298: 526, 2002.
63. Mita AC, Mita MM, Nawrocki ST, Giles FJ. Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res 14: 5000-5005, 2008.
64. Montolio M, Tellez N, Biarnes M, Soler J, Montanya E. Short-term culture with the caspase inhibitor z-VAD. fmk reduces beta cell apoptosis in transplanted islets and improves the metabolic outcome of the graft. Cell Transplant 14: 59-65, 2005.
65. Muzio M, Chinnaiyan AM, Kischkel FC, O'Rouke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85: 817-827, 1996.
66. Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, Munday NA, Raju SM, Smulson ME, Yamin TT, Yu VL, Miller DK. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376: 37-43, 1995.
67. Notkins AL, Lernmark A. Autoimmune type 1 diabetes: resolved and unresolved issues. J Clin Invest 108: 1247-1252, 2001.
68. Okuyama R, Nguyen BC, Talora C, Ogawa E, Tommasi di Vignano A, Lioumi M, Chiorino G, Tagami H, Woo M, Dotto GP. High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism. Dev Cell 6: 551-562, 2004.
69. O'Riordan MX, Bauler LD, Scott FL, Duckett CS. Inhibitor of apoptosis (IAP) proteins in eukaryotic evolution and development: a model of thematic conservation. Dev Cell 15: 497-508, 2008.
70. Parone PA, James D, Martinou JC. Mitochondria: regulating the inevitable. Biochimie 84: 105-111, 2002.
71. Pelengaris S, Khan M, Evan GI. Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109: 321-334, 2002.
72. Peter ME, Budd RC, Desbarats J, Hedrick SM, Hueber A, Newell MK, Owen LB, Pope RM, Tschopp J, Wajant H, Wallach D, Wiltrout RH, Zornig M, Lynch DH. The CD95 receptor apoptosis revisited. Cell 129: 447-450, 2007.
73. Pimenta W, Korytkowski M, Mitrakou A, Jenssen T, Yki-Jarvinen H, Evron W, Dailey G, Gerich J. Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. JAMA 273: 1855-1861, 1995.
74. Plesner A, Liston P, Tan R, Korneluk RG, Verchere CB. The X-linked inhibitor of apoptosis protein enhances survival of murine islet allografts. Diabetes 54: 2533-2540, 2005.
75. Radziszewska A, Schroer SA, Choi D, Tajmir P, Radulovich N, Ho JC, Wang L, Liadis N, Hakem R, Tsao MS, Penn LZ, Evan GI, Woo M. Absence of caspase-3 protects pancreatic β-cells from c-Myc induced apoptosis without leading to tumor formation. J Biol Chem 284: 10947-10956, 2009.
76. Rhodes CJ. Type 2 diabetes - a matter of β-cell life and death? Science 307: 380-384, 2005.
77. Sakuraba H, Mizukami H, Yagihashi N, Wada R, Hanyu C, Yagihashi S. Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients. Diabetologia 45: 85-96, 2002.
78. Salmena L, Lemmers B, Hakem A, Matysiak-Zablocki E, Murakami K, Au PY, Berry DM, Tamblyn L, Shehabeldin A, Migon E, Wakeham A, Bouchard D, Yeh WC, McGlade JC, Ohashi PS, Hakem R. Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. Genes Dev 17: 883-895, 2003.
79. Salvesen GS, Duckett CS. IAP proteins: blocking the road to death's door. Nat Rev Mol Cell Biol 3: 401-410, 2002.
80. Scaffidi C, Smitz I, Krammer PH, Peter ME. The role of c-FLIP in modulation of CD95-induced apoptosis. J Biol Chem 274: 1541-1548, 1999.
81. Schumann DM, Maedler K, Franklin I, Konrad D, Storling J, Boni-Schnetzler M, Gjinovci A, Kurrer MO, Gauthier BR, Bosco D, Andres A, Berney T, Greter M, Becher B, Chervonsky AV, Halban PA, Mandrup-Poulsen T, Wollheim CB, Donath MY. The Fas pathway is involved in pancreatic beta cell secretory function. Proc Natl Acad Sci USA 104: 2861-2866, 2007.
82. Scott FL, Denault JB, Riedl SJ, Shin H, Renatus M, Salvesen GS. XIAP inhibits caspase-3 and -7 using two binding sites: evolutionarily conserved mechanism of IAPs. EMBO J 24: 645-655, 2005.
83. Slee EA, Adrain C, Martin SJ. Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J Biol Chem 10: 7320-7326, 2001.
84. Stupack DG, Teitz T, Potter MD, Mikolon D, Houghton PJ, Kidd VJ, Lahti JM, Cheresh DA. Potentiation of neuroblastoma metastasis by loss of caspase-8. Nature 439: 95-99, 2006.
85. Szymczyk KH, Freeman TA, Adams CS, Srinivas V, Steinbeck MJ. Active caspase-3 is required for osteoclast differentiation. J Cell Physiol 209: 836-844, 2006.
86. Taira K, Hiroyasu S, Shiraishi M, Muto Y, Kojib T. Role of the Fas system in liver regeneration after a partial hepatectomy in rats. Eur Surg Res 33: 334-341, 2001.
87. Tan Y, Demeter MR, Ruan H, Comb MJ. BAD Ser-155 phosphorylation regulates BAD/Bcl-XL interaction and cell survival. J Biol Chem 275: 25865-25869, 2000.
88. Tewari M, Quan LT, O'Rourke T, Desnoyers S, Zeng Z, Beidler DR, Poirier GG, Salvesen GS, Dixit VM. Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly (ADP-ribose) polymerase. Cell 81: 801-809, 1995.
89. Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science 267: 1456-1462, 1995.
90. Vaux DL, Weissman IL, Kim SK. Prevention of programmed cell death in Caenorhabditis elegans by human Bcl-2. Science 258: 1955-1957, 1992.
91. Verhagen AM, Coulson EJ, Vaux DL. Inhibitor of apoptosis proteins and their relatives: IAPs and other BIRPs. Genome Biol 2: REVIEWS 3009, 2001.
92. Wang J, Chun HJ, Wong W, Spencer DM, Lenardo MJ. caspase-10 is an initiator caspase in death receptor signaling. Proc Natl Acad Sci USA 98: 13884-13888, 2001.
93. Woo M, Hakem R, Furlonger C, Hakem A, Duncan GS, Sasaki T, Bouchard D, Lu L, Wu GE, Paige CJ, Mak TW. caspase-3 regulates cell cycle in B cells: a consequence of substrate specificity. Nat Immunol 4: 1016-1022, 2003.
94. Wu X, Wang L, Schroer SA, Choi D, Chen P, Okada H, Woo M. Perinatal survivin is essential for the establishment of pancreatic beta cell mass in mice. Diabetologia 52: 2130-2141, 2009.
95. Yamada K, Ichikawa F, Ishiyama-Shigemoto S, Yuan X, Nonaka K. Essential role of caspase-3 in apoptosis of mouse beta-cells transfected with human Fas. Diabetes 48: 478-483, 1999.
96. Yoon KH, Ko SH, Cho JH, Lee JM, Ahn YB, Song KH, Yoo SJ, Kang MI, Cha BY, Lee KW, Son HY, Kang SK, Kim HS, Lee IK, Bonner-Weir S. Selective beta-cell loss and alpha-cell expansion in patients with Type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab 88: 2300-2308, 2003.
97. Yu L, Wan F, Dutta S, Welsh S, Liu Z, Freundt E, Baehrecke EH, Lenardo M. Autophagic programmed cell death by selective catalase degradation. Proc Natl Acad Sci USA 103: 4952-4957, 2006.
98. Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz The C HR. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 75: 641-652, 1993.
99. Zhou YP, Pena JC, Roe MW, Mittal A, Levisetti M, Baldwin AC, Pugh W, Ostrega D, Ahmed N, Bindokas VP, Philipson LH, Hanahan D, Thompson CB, Polonsky KS. Overexpression of Bcl-x(L) in β-cells prevents cell death but impairs mitochondrial signal for insulin secretion. Am J Physiol Endocrinol Metab 278: E340-E351, 2000.