alpha B-crystallin gene induction and phosphorylation by MKK6-activated p38. A potential role for alpha B-crystallin as a target of the p38 branch of the cardiac stress response.
The MAPK kinase MKK6 selectively stimulates p38 MAPK and confers protection against stress-induced apoptosis in cardiac myocytes. However, the events lying downstream of p38 that mediate this protection are unknown. The small heat shock protein, alphaB-crystallin, which is expressed in only a few cell types, including cardiac myocytes, may participate in MKK6-mediated cytoprotection. In the present study, we showed that, in cultured cardiac myocytes, expression of MKK6(Glu), an active form of MKK6, led to p38-dependent increases in alphaB-crystallin mRNA, protein, and transcription. MKK6(Glu) also induced p38-dependent activation of the downstream MAPK-activated protein kinase, MAPKAP-K2, and the phosphorylation of alphaB-crystallin on serine-59. Initially, exposure of cells to the hyperosmotic stressor, sorbitol, stimulated MKK6, p38, and MAPKAP-K2 and increased phosphorylation of alphaB-crystallin on serine 59. However, after longer times of exposure to sorbitol, the cells began to undergo apoptosis. This sorbitol-induced apoptosis was increased when p38 was inhibited in a manner that would block alphaB-crystallin induction and phosphorylation. Thus, under these conditions, the activation of MKK6, p38, and MAPKAP-K2 by sorbitol can provide a degree of protection against stress-induced apoptosis. Supporting this view was the finding that sorbitol-induced apoptosis was nearly completely blocked in cells expressing MKK6(Glu). Therefore, the cytoprotective effects of MKK6 in cardiac myocytes are due, in part, to phosphorylation of alphaB-crystallin on serine 59 and to the induction of alphaB-crystallin gene expression.
Hoover
H E
HE
SDSU Heart Institute and the Department of Biology, San Diego State University, San Diego, California 92182, USA.
Thuerauf
D J
DJ
Martindale
J J
JJ
Glembotski
C C
CC
D000818:Animals; D017209:Apoptosis; D018053:Arsenites / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured / Q000187:drug effects; D003459:Crystallins / Q000096:biosynthesis / Q000235:genetics*; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D047908:Intracellular Signaling Peptides and Proteins; D048669:MAP Kinase Kinase 6; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins; D010766:Phosphorylation; D020011:Protective Agents; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020218:Response Elements; D026362:Serum Response Factor; D015398:Signal Transduction; D013012:Sorbitol / Q000494:pharmacology; D013312:Stress, Physiological / Q000378:metabolism*; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2
D018053:Arsenites; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D003459:Crystallins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D048669:MAP Kinase Kinase 6; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D020011:Protective Agents; D017346:Protein Serine-Threonine Kinases; D026362:Serum Response Factor; D013012:Sorbitol; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C015001:arsenite