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BMC Chemical Biology

, 8:2

First Online: 01 August 2008Received: 17 April 2008Accepted: 01 August 2008

Abstract

BackgroundIntracellular free calcium Cai is a key element in apoptotic signaling and a number of calcium-dependent apoptosis pathways have been described. We here used a chemical biology strategy to elucidate the relative importance of such different pathways.

ResultsA set of 40 agents -bioprobes- that induce apoptosis was first identified by screening of a chemical library. Using p53, AP-1, NFAT and NF-κB reporter cell lines, these bioprobes were verified to induce different patterns of signaling. Experiments using the calcium chelator BAPTA-AM showed that Ca was involved in induction of apoptosis by the majority of the bioprobes and that Ca was in general required several hours into the apoptosis process. Further studies showed that the calmodulin pathway was an important mediator of the apoptotic response. Inhibition of calmodulin kinase II CaMKII resulted in more effective inhibition of apoptosis compared to inhibition of calpain, calcineurin-PP2B or DAP kinase. We used one of the bioprobes, the plant alkaloid helenalin, to study the role of CaMKII in apoptosis. Helenalin induced CaMKII, ASK1 and Jun-N-terminal kinase JNK activity, and inhibition of these kinases inhibited apoptosis.

ConclusionOur study shows that calcium signaling is generally not an early event during the apoptosis process and suggests that a CaMKII-ASK1 signaling mechanism is important for sustained JNK activation and apoptosis by some types of stimuli.

AbbreviationsCaMCalmodulin

CaMKIICalmodulin-dependent Kinase II

RyRRyanodine receptor

InsP3Inositol 1,4,5-triphosphate

DAPKDeath-associated protein kinase

ASK-1Apoptosis signaling kinase 1

TNFTumor necrosis factor

NFATNuclear factor of activated T-cells

Electronic supplementary materialThe online version of this article doi:10.1186-1472-6769-8-2 contains supplementary material, which is available to authorized users.

Maria Hägg Olofsson, Aleksandra Mandic Havelka contributed equally to this work.

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Autor: Maria Hägg Olofsson - Aleksandra Mandic Havelka - Slavica Brnjic - Maria C Shoshan - Stig Linder

Fuente: https://link.springer.com/







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