This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Huo, J. Articles by Li, G. Search for Related Content PubMed PubMed Citation Articles by Huo, J. Articles by Li, G.

Activation of Caspase-2 Mediates the Apoptosis Induced by GTP-Depletion in Insulin-Secreting (HIT-T15) Cells*

Cardiovascular Research Institute (J.H., R.-H.L., G.L.), National University Medical Institutes, National University of Singapore, Singapore 117597; and Pacific Northwest Research Institute (S.A.M.), Seattle, Washington 98122

Address all correspondence and requests for reprints to: Guodong Li, National University Medical Institutes, MD11 02-01, 10 Medical Drive, Singapore 117597, Singapore. E-mail: . nmiligd{at}nus.edu.sg

This study investigated the possible involvement of a specific caspase(s) (a family of aspartate-specific cysteine proteases) in programmed cell death of islet ß-cells due to sustained GTP depletion. Treatment (up to 48 h) with 3 µg/ml mycophenolic acid (MPA), which specifically depletes intracellular guanine nucleotides, reduced cell-cycle progression from G1 phase into S and G2/M phases (as assessed by flow cytometry) and, subsequently, induced apoptosis of HIT-15 cells (transformed pancreatic ß-cells). The latter was accompanied by a marked increase of caspase-2 activity (+343%) and moderate activation of caspase-9 (+150%) and caspase-3 (+145%). Importantly, only caspase-2 activation preceded induction of apoptosis. There was no change in activity of caspase-1, -4, -5, -6, and -8. Release of the mitochondrial protein cytochrome c into cytosol was also observed at a late stage. Cotreatment of cells with a permeable pan-caspase inhibitor (Z-VAD-FMK) blocked GTP depletion-induced cell death in a dose-dependent manner. A specific caspase-2 inhibitor (Z-VDVAD-FMK), but not a caspase-3 inhibitor (DEVD-CHO), was also capable of restoring cell viability. Interestingly, activation of caspase-2 leads to caspase-3 activation because the caspase-2 inhibitor abrogated caspase-3 activity. Our results indicate that, while activation of multiple caspases are involved in the execution phase of GTP depletion-induced apoptosis, caspase-2 appears to play the major role in the initiation of this program. This study revealed a novel, caspase-2 mediated form of apoptosis that may be consequent to impaired mitogenesis.

This article has been cited by other articles:

				B. Chaigne-Delalande, G. Guidicelli, L. Couzi, P. Merville, W. Mahfouf, S. Bouchet, M. Molimard, B. Pinson, J.-F. Moreau, and P. Legembre The Immunosuppressor Mycophenolic Acid Kills Activated Lymphocytes by Inducing a Nonclassical Actin-Dependent Necrotic Signal J. Immunol., December 1, 2008; 181(11): 7630 - 7638. [Abstract] [Full Text] [PDF]

				M Asfari, S Berta, S Coffy, M Kergoat, C Charon, and A Audet Short-term treatment with mycophenolic acid and tacrolimus is tolerogenic for INS-1 cell clone transplantation and the deleterious effects of the drugs are limited: in vivo and in vitro studies J. Endocrinol., July 1, 2005; 186(1): 213 - 220. [Abstract] [Full Text] [PDF]

				W. Chen, K. V. Salojin, Q.-S. Mi, M. Grattan, T. C. Meagher, P. Zucker, and T. L. Delovitch Insulin-Like Growth Factor (IGF)-I/IGF-Binding Protein-3 Complex: Therapeutic Efficacy and Mechanism of Protection against Type 1 Diabetes Endocrinology, February 1, 2004; 145(2): 627 - 638. [Abstract] [Full Text] [PDF]

				J. A. Maassen, Leen. M. 't Hart, E. van Essen, R. J. Heine, G. Nijpels, R. S. Jahangir Tafrechi, A. K. Raap, G. M.C. Janssen, and H. H.P.J. Lemkes Mitochondrial Diabetes: Molecular Mechanisms and Clinical Presentation Diabetes, February 1, 2004; 53(90001): S103 - 109. [Abstract] [Full Text]

				Y.-C. Fu, C.-S. Chi, S.-C. Yin, B. Hwang, Y.-T. Chiu, and S.-L. Hsu Norepinephrine induces apoptosis in neonatal rat endothelial cells via down-regulation of Bcl-2 and activation of {beta}-adrenergic and caspase-2 pathways Cardiovasc Res, January 1, 2004; 61(1): 143 - 151. [Abstract] [Full Text] [PDF]

				I. Maestre, J. Jordan, S. Calvo, J. A. Reig, V. Cena, B. Soria, M. Prentki, and E. Roche Mitochondrial Dysfunction Is Involved in Apoptosis Induced by Serum Withdrawal and Fatty Acids in the {beta}-Cell Line Ins-1 Endocrinology, January 1, 2003; 144(1): 335 - 345. [Abstract] [Full Text] [PDF]