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Suppression or induction of apoptosis by opposing pathways downstream from calcium-activated calcineurin
1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Abstract:
Ca(2+)-mobilizing compounds such as the Ca(2+) ionophore A23187 or the endoplasmic reticulum Ca(2+) ATPase inhibitor thapsigargin can suppress or induce apoptosis in the same cells. The use of different calcineurin inhibitors has shown that both suppression and induction of apoptosis by the Ca(2+)-mobilizing compounds were mediated by calcineurin activation. Ca(2+)-mobilizing compounds activated p38 and p44/42 mitogen-activated protein kinases (MAPKs). Induction of apoptosis by the Ca(2+)-mobilizing compounds was suppressed by an inhibitor of p38 MAPK but not by an inhibitor of p44/42 MAPK. These MAPK inhibitors did not suppress apoptosis induction by wild-type p53 or by withdrawal of IL-6 from IL-6-dependent cells that are mediated by calcineurin-independent pathways. These MAPK inhibitors also did not affect the ability of Ca(2+)-mobilizing compounds to suppress apoptosis. The results indicate that (i) Ca(2+)- mobilizing compounds activate different and opposing pathways that diverge downstream from calcineurin activation that can either suppress or induce apoptosis in the same cells; (ii) p38 MAPK but not p44/42 MAPK is involved in induction of apoptosis but not in its suppression by the Ca(2+)-mobilizing compounds; and (iii) neither p38 nor p44/42 MAPKs mediate induction of apoptosis by some calcineurin-independent pathways.
Insights
Calcium-mobilizing compounds trigger opposing cell death pathways via calcineurin activation. p38 MAPK mediates apoptosis induction, but not suppression, by these compounds.
Area of Science:
- Cellular biology
- Molecular signaling
- Apoptosis research
Background:
- Calcium homeostasis is critical for cell survival and death.
- Calcium-mobilizing agents can paradoxically induce or suppress apoptosis.
- Calcineurin signaling plays a key role in mediating these opposing effects.
Purpose of the Study:
- To elucidate the distinct signaling pathways activated by calcium-mobilizing compounds.
- To investigate the role of mitogen-activated protein kinases (MAPKs) in calcium-mediated apoptosis.
- To differentiate the roles of p38 MAPK and p44/42 MAPK in apoptosis induction versus suppression.
Main Methods:
- Utilized calcium ionophores (A23187) and endoplasmic reticulum calcium ATPase inhibitors (thapsigargin).
- Employed calcineurin inhibitors to assess pathway mediation.
- Investigated the effects of p38 MAPK and p44/42 MAPK inhibitors on apoptosis.
- Examined apoptosis induction via calcineurin-independent pathways (wild-type p53, IL-6 withdrawal).
Main Results:
- Calcium-mobilizing compounds activate both pro-apoptotic and anti-apoptotic pathways downstream of calcineurin.
- p38 MAPK inhibition suppressed apoptosis induction by these compounds, while p44/42 MAPK inhibition did not.
- MAPK inhibitors did not affect apoptosis induced by calcineurin-independent pathways or the suppression of apoptosis by calcium-mobilizing compounds.
Conclusions:
- Calcium-mobilizing compounds activate divergent pathways from calcineurin, leading to either apoptosis induction or suppression.
- p38 MAPK is specifically involved in the induction of apoptosis, not its suppression, by these agents.
- p38 and p44/42 MAPKs are not involved in calcineurin-independent apoptosis induction pathways.