This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Devireddy, L. R. Articles by Green, M. R. Search for Related Content PubMed PubMed Citation Articles by Devireddy, L. R. Articles by Green, M. R.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, July 2003, p. 4532-4541, Vol. 23, No. 13
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.13.4532-4541.2003
Copyright © 2003, 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 17 October 2002/ Returned for modification 28 January 2003/ Accepted 7 April 2003

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: michael.green{at}umassmed.edu.

---

Molecular and Cellular Biology, July 2003, p. 4532-4541, Vol. 23, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.13.4532-4541.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Lin, K.-R., Lee, S.-F., Hung, C.-M., Li, C.-L., Yang-Yen, H.-F., Yen, J. J. Y. (2007). Survival Factor Withdrawal-induced Apoptosis of TF-1 Cells Involves a TRB2-Mcl-1 Axis-dependent Pathway. J. Biol. Chem. 282: 21962-21972 [Abstract] [Full Text]  
• Gong, D., Malek, T. R. (2007). Cytokine-Dependent Blimp-1 Expression in Activated T Cells Inhibits IL-2 Production. J. Immunol. 178: 242-252 [Abstract] [Full Text]  
• Sukiennicki, T. L., Fowell, D. J. (2006). Distinct Molecular Program Imposed on CD4+ T Cell Targets by CD4+CD25+ Regulatory T Cells. J. Immunol. 177: 6952-6961 [Abstract] [Full Text]  
• Cao, Q., Xia, Y., Azadniv, M., Crispe, I. N. (2004). The E2F-1 Transcription Factor Promotes Caspase-8 and Bid Expression, and Enhances Fas Signaling in T Cells. J. Immunol. 173: 1111-1117 [Abstract] [Full Text]