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Activation of activating transcription factor 2 by p38 MAP kinase during apoptosis induced by human amylin in cultured pancreatic β‐cells
Author(s) -
Zhang Shaoping,
Liu Hong,
Liu Junxi,
Tse Cynthia A.,
Dragunow Michael,
Cooper Garth J. S.
Publication year - 2006
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2006.05386.x
Subject(s) - p38 mitogen activated protein kinases , microbiology and biotechnology , kinase , mitogen activated protein kinase kinase , ask1 , protein kinase a , map kinase kinase kinase , mitogen activated protein kinase , activating transcription factor 2 , c jun , biology , chemistry , transcription factor , biochemistry , gene expression , promoter , gene
Amylin‐mediated islet β‐cell death is implicated in diabetogenesis. We previously reported that fibrillogenic human amylin (hA) evokes β‐cell apoptosis through linked activation of Jun N‐terminal kinase 1 (JNK 1) and a caspase cascade. Here we show that p38 kinase [p38 mitogen‐activated protein (MAP) kinase] became activated by hA treatment of cultured β‐cells whereas extracellular signal‐regulated kinase (ERK) did not; by contrast, nonfibrillogenic rat amylin (rA) altered neither. Pretreatment with the p38 kinase‐inhibitor SB203580 decreased hA‐induced apoptosis and caspase‐3 activation by ∼30%; as did combined SB203580 and JNK inhibitor I, by about 70%; and the combination of SB203580, the JNK inhibitor I and a caspase‐8 inhibitor, by 100%. These findings demonstrate the requirement for concurrent activation of the p38 kinase, JNK and caspase‐8 pathways. We further showed that hA elicits time‐dependent activation of activating transcription factor 2 (ATF‐2), which was largely suppressed by SB203580, indicating that this activation is catalyzed mainly by p38 kinase. Furthermore, hA‐induced apoptosis was suppressed by specific antisense ATF‐2 , and increased phospho‐ATF‐2 (p‐ATF‐2) was associated with increased CRE (cAMP‐response element) DNA binding and CRE ‐mediated transcriptional activity, as well as enhancement of c‐jun promoter activation. We also detected changes in the phosphorylation status and composition of the CRE complex that may play important roles in regulation of distinct downstream target genes. These studies establish p38 MAP kinase‐mediated activation of ATF‐2 as a significant mechanism in hA‐evoked β‐cell death, which may serve as a target for pharmaceutical intervention and effective suppression of β‐cell failure in type‐2 diabetes.