This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Droin, N. Articles by Bertrand, R. Search for Related Content PubMed PubMed Citation Articles by Droin, N. Articles by Bertrand, R.

Identification of a Caspase-2 Isoform that Behaves as an Endogenous Inhibitor of the Caspase Cascade¹

Research Centre of the University of Montreal Hospital Centre, Notre Dame Hospital, Montreal Cancer Institute, Montreal, Quebec, H2L 4M1, Canada [N. D., M. B., R. B.], and INSERM U517, Faculty of Medicine and Pharmacy, 21033 Dijon, France [N. D., E. S.]

Procaspase-2 is one of the aspartate-specific cysteine proteases that are activated in response to various apoptotic stimuli. Two isoforms of human procaspase-2 have been described initially. Overexpression of the long isoform (caspase-2L) promotes cell death whereas the short isoform (caspase-2S) antagonizes some apoptotic pathways. In the present study, we identified two additional CASP-2 mRNAs, designated CASP-2L-Pro and CASP-2S-Pro. The proteins encoded by these isoforms corresponded to the prodomain of procaspase-2L and -2S, in which the last -helix of their caspase recruitment domains was deleted. Caspase-2L-Pro mRNA and protein were detected in a series of human tissues and cell lines. Yeast 2-hybrid assays and immunoprecipitation studies indicated that caspase-2L-Pro can interact with procaspase-2L and the adaptor protein RAIDD/CRADD, but not with FADD/MORT1 or APAF-1 adaptor proteins. The addition of recombinant caspase-2L-Pro negatively interfered with cytochrome c/dATP-mediated activation of the caspase cascade in a cell-free system. In transient expression studies of human B lymphoma Namalwa cells, overexpression of caspase-2L-Pro weakly induced apoptosis, which was prevented by a D83A/E87A double mutation. In stable selected CASP-2L-Pro-transfected Namalwa cells, overexpression of caspase-2L-Pro delayed apoptotic DNA fragmentation induced by death receptor agonists (anti-Fas antibodies, tumor necrosis factor-) and DNA topoisomerase I- (camptothecin) and II- (etoposide) inhibitors, and prevented etoposide-induced activation of the caspase cascade. These inhibitory effects were not observed in stable transfected cells expressing the D83A/E87A double mutant. Altogether, these data indicated that the caspase-2L-Pro isoform functions as an endogenous apoptosis inhibitory protein that antagonizes caspase activation and cell death.

This article has been cited by other articles:

				K. Fushimi, P. Ray, A. Kar, L. Wang, L. C. Sutherland, and J. Y. Wu Up-regulation of the proapoptotic caspase 2 splicing isoform by a candidate tumor suppressor, RBM5 PNAS, October 14, 2008; 105(41): 15708 - 15713. [Abstract] [Full Text] [PDF]

				C. C. Chua, X. Liu, J. Gao, R. C. Hamdy, and B. H. L. Chua Multiple actions of pifithrin-{alpha} on doxorubicin-induced apoptosis in rat myoblastic H9c2 cells Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2606 - H2613. [Abstract] [Full Text] [PDF]

				B. L. Kee Id3 Induces Growth Arrest and Caspase-2-Dependent Apoptosis in B Lymphocyte Progenitors J. Immunol., October 1, 2005; 175(7): 4518 - 4527. [Abstract] [Full Text] [PDF]

				S. Liu and R. B. Altman Large scale study of protein domain distribution in the context of alternative splicing Nucleic Acids Res., August 15, 2003; 31(16): 4828 - 4835. [Abstract] [Full Text] [PDF]

				B. H. Han, D. Xu, J. Choi, Y. Han, S. Xanthoudakis, S. Roy, J. Tam, J. Vaillancourt, J. Colucci, R. Siman, et al. Selective, Reversible Caspase-3 Inhibitor Is Neuroprotective and Reveals Distinct Pathways of Cell Death after Neonatal Hypoxic-ischemic Brain Injury J. Biol. Chem., August 9, 2002; 277(33): 30128 - 30136. [Abstract] [Full Text] [PDF]

				D. Himeji, T. Horiuchi, H. Tsukamoto, K. Hayashi, T. Watanabe, and M. Harada Characterization of caspase-8L: a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade Blood, May 13, 2002; 99(11): 4070 - 4078. [Abstract] [Full Text] [PDF]