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Mol. Cell. Biol. 23 (13): 4532-4541

Copyright © 2003 by the American Society for Microbiology. All rights reserved.

Transcriptional Program of Apoptosis Induction following Interleukin 2 Deprivation: Identification of RC3, a Calcium/Calmodulin Binding Protein, as a Novel Proapoptotic Factor

Laxminarayana R. Devireddy and Michael R. Green*

Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Received for publication 17 October 2002. Revision received 28 January 2003. Accepted for publication 7 April 2003.

Abstract: Apoptosis of mature T lymphocytes preserves immune system homeostasis by counteracting transient increases in T-cell number. This process is regulated, at least in part, by the cytokine interleukin 2 (IL-2): T cells deprived of IL-2 undergo apoptosis. The mechanism of apoptosis induction by IL-2 deprivation remains to be determined but is known to require RNA synthesis, implying the existence of transcriptionally activated genes whose products induce cell death. To identify such genes, we have performed expression profiling in IL-2-dependent T cells following cytokine deprivation. Our results reveal an intricate transcriptional program entailing the induction of known proapoptotic factors and the simultaneous repression of known antiapoptotic factors. Surprisingly, one gene whose transcription substantially increased was RC3 (also called neurogranin), which encodes a calmodulin binding protein thought to be a neural-specific factor involved in learning and memory. We show that ectopic expression of RC3 in IL-2-dependent T cells increases the intracellular Ca2+ concentration and induces apoptosis even in the presence of cytokine. Buffering the Ca2+ increase with the cytoplasmic Ca2+ chelator BAPTA-AM [1,2-bis(2-aminophenoxy)ethane-N,N,N1,N-tetraacetic acid] blocks RC3-induced apoptosis, indicating that the rise in intracellular Ca2+ is required for apoptotic death. RC3 mutants unable to bind calmodulin fail to increase intracellular Ca2+ levels and to induce apoptosis. Based upon these results, we propose that IL-2 deprivation raises the level of RC3 and other apoptotic factors, which induce apoptosis by increasing the intracellular Ca2+ concentration.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605. Phone: (508) 856-5331. Fax: (508) 856-5473. E-mail:{at}

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