Promoting a Deadly Rise in Calcium

Science's STKE  24 Jun 2003:
Vol. 2003, Issue 188, pp. tw238
DOI: 10.1126/stke.2003.188.tw238

Devireddy and Green used expression profiling to uncover genes that were transcriptionally activated in response to interleukin 2 (IL-2) deprivation and identified a protein implicated in learning and memory as a novel proapoptotic factor in T lymphocytes. After termination of an immune response, the expanded population of T cells is eliminated through apoptosis. T cell apoptosis in response to IL-2 deprivation requires transcriptional activation; however, the details remain unclear. Devireddy and Green identified genes whose transcription was activated or inhibited after IL-2 withdrawal in an IL-2-dependent T cell line. Among the genes that were activated was RC3 (or neurogranin), whose protein product is a calmodulin (CaM)-binding protein, previously considered to be neuron-specific. Other IL-2-dependent cells also upregulated RC3 following IL-2 deprivation; whereas cells dependent on other cytokines did not show this response after cytokine deprivation nor did apoptotic cells from an IL-2-independent T cell line. RC3 overexpression promoted apoptosis in T cell lines; mutational analysis indicated that this depended on an intact CaM-binding domain. Fluorescent imaging with the Ca2+-indicator fura-2 AM showed that both IL-2 deprivation and overexpression of RC3 led to similar increases in intracellular Ca2+ concentration. Blocking this increase with a Ca2+ chelator inhibited apoptosis. A second CaM-binding protein that was previously identified as a proapoptotic factor in various cell types was also up-regulated, leading the authors to propose a model whereby IL-2 withdrawal promotes apoptosis through multiple pathways involving CaM segregation and a consequent deadly rise in intracellular Ca2+.

L. Devireddy, M. R. Green, Transcriptional program of apoptosis induction following interleukin 2 deprivation: Identification of RC3, a calcium/calmodulin binding protein, as a novel proapoptotic factor. Mol. Cell. Biol. 23, 4532-4541 (2003). [Abstract] [Full Text]