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J Biol Chem, Vol. 275, Issue 9, 6417-6420, March 3, 2000

Calcineurin Is Downstream of the Inositol 1,4,5-Trisphosphate Receptor in the Apoptotic and Cell Growth Pathways*

Thottala Jayaraman and Andrew R. MarksDagger §

From the Departments of Medicine and Dagger  Pharmacology, Molecular Cardiology Program, College of Physicians and Surgeons of Columbia University, New York, New York 10032

The inositol 1,4,5-trisphosphate receptor (IP3R) is a calcium (Ca2+) release channel found on the endoplasmic reticulum of virtually all types of cells. Human T lymphocytes (Jurkat) that are made deficient in IP3R do not generate Ca2+ signals in response to T cell receptor stimulation, fail to translocate the nuclear factor for activated T cells to the nucleus, and are remarkably resistant to induction of apoptosis with CD95 (Fas), dexamethasone, gamma  irradiation, and T cell receptor stimulation using anti-CD3 antibody. Expression of constitutively active calcineurin A in IP3R-deficient T cells restored nuclear factor for activated T cells translocation to the nucleus and dephosphorylation of Bad and rendered the cells sensitive to apoptotic inducers. Induction of apoptosis required both active calcineurin A (Delta CnA) and activation-dependent colocalization of CnA with its substrate. Thus, the Ca2+-dependent phosphatase calcineurin (CnA) is downstream of the IP3R in both the cell growth and apoptotic signaling pathways.

* This work was supported by National Institutes of Health (NIH) Grants AI39794, HL56180, and HL61503 (to A. R. M.), the American Heart Association (to A. R. M. and T. J.), the Richard and Lynne Kaiser Family Foundation (to A. R. M.), and by NIH Shared Instrumentation Grants 1S10 RR10506 and 5P30 CA13696.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Molecular Cardiology Program, P&S 9-401, Columbia University, 630 West 168th St., New York, NY 10032. Tel.: 212-305-0270; Fax: 212-305-3690; E-mail: arm42@columbia.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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