TAILIEUCHUNG - Báo cáo khoa học: Activation of activating transcription factor 2 by p38 MAP kinase during apoptosis induced by human amylin in cultured pancreatic b-cells

Amylin-mediated isletb-cell death is implicated in diabetogenesis. We pre-viously reported that fibrillogenic human amylin (hA) evokesb-cell apopto-sis through linked activation of Jun N-terminal kinase 1 (JNK 1) and a caspase cascade. Here we show that p38 kinase [p38 mitogen-activated pro-tein (MAP) kinase] became activated by hA treatment of cultured b-cells whereas extracellular signal-regulated kinase (ERK) did not; | ỊFEBS Journal Activation of activating transcription factor 2 by p38 MAP kinase during apoptosis induced by human amylin in cultured pancreatic b-cells Shaoping Zhang1 Hong Liu1 Junxi Liu1 Cynthia A. Tse1 Michael Dragunow2 and Garth J. S. Cooper1 1 The Schoolof BiologicalSciences Faculty of Science University of Auckland New Zealand 2 Department of Pharmacology and ClinicalPharmacology Faculty of Medicaland Health Sciences University of Auckland New Zealand Keywords activating transcription factor 2 amylin b-cellapoptosis p38 kinase type-2 diabetes Correspondence G. J. S. Cooper Schoolof Biological Sciences University of Auckland Level4 3A Symonds Street Private Bag 92019 Auckland New Zealand Fax 64 93737045 Tel 64 93737599 ext. 87239 E-mail Received 3 May 2006 accepted 16 June 2006 doi Amylin-mediated islet b-cell death is implicated in diabetogenesis. We previously reported that fibrillogenic human amylin hA evokes b-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 b-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 .

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