UMMS Affiliation

Howard Hughes Medical Institute; Program in Molecular Medicine; Program in Gene Function and Expression

Publication Date

6-17-2003

Document Type

Article

Subjects

*Apoptosis; Calcium; Calmodulin-Binding Proteins; Cell Death; DNA, Complementary; Egtazic Acid; Flow Cytometry; Genetic Vectors; Humans; Interleukin-2; Jurkat Cells; Nerve Tissue Proteins; Neurogranin; Oligonucleotide Array Sequence Analysis; Plasmids; Protein Structure, Tertiary; RNA; Spectrometry, Fluorescence; Time Factors; Trans-Activation (Genetics); *Transcription, Genetic; Transfection

Disciplines

Life Sciences | Medicine and Health Sciences

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 Ca(2+) concentration and induces apoptosis even in the presence of cytokine. Buffering the Ca(2+) increase with the cytoplasmic Ca(2+) 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 Ca(2+) is required for apoptotic death. RC3 mutants unable to bind calmodulin fail to increase intracellular Ca(2+) 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 Ca(2+) concentration.

Rights and Permissions

Citation: Mol Cell Biol. 2003 Jul;23(13):4532-41.

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Molecular and cellular biology acetoxymethyl ester)

PubMed ID

12808095

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