Transcriptional program of apoptosis induction following interleukin 2 deprivation: Identification of RC3, a calcium/calmodulin binding protein, as a novel proapoptotic factor
Transcriptional program of apoptosis induction following interleukin 2 deprivation: Identification of RC3, a calcium/calmodulin binding protein, as a novel proapoptotic factor
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DOI：
10.1128/mcb.23.13.4532-4541.2003
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发表时间：
2003-07-01
影响因子：
5.3
通讯作者：
Green, MR
中科院分区：
文献类型：
--
作者：
Devireddy, LR;Green, MR
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 intracellullar 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.
