title: Caspase-3 mediated cleavage of MEKK1 promotes p53 transcriptional activity.
abstract: Myocardial ischemia/reperfusion (IR) induces myocyte apoptosis, and the pro-apoptotic/tumor suppressor protein p53 may contribute to this process. However, the signaling mechanism by which IR induces p53 activation remains largely unknown. Here, we show that MEKK1 undergoes proteolytic cleavage in a caspase-3 dependent manner in both in vivo and in vitro models of ischemic injury. Overexpression studies both in vivo and in vitro indicated that the caspase-3 mediated cleavage of MEKK1 promotes phosphorylation and transcriptional activity of p53. In addition, caspase-3 inhibited the ability of the wild-type full-length form of MEKK1 to activate ATF2, suggesting that caspase-3, by way of proteolytic cleavage, abrogates the ability of MEKK1 to signal JNK. We propose that IR induces caspase-3 mediated proteolytic cleavage of MEKK1 and promotes p53 transcriptional activity via JNK-independent mechanisms, which in turn may contribute to pathological insults associated with IR injury, such as myocyte apoptosis.
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, 07103, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Zebrowski
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Alcendor
authors.forename: Lorrie A
authors.initials: LA
authors.lastname: Kirshenbaum
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D007511:Ischemia / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury; D015398:Signal Transduction; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D051698:Activating Transcription Factor 2; C497107:Atf2 protein, rat; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; D048728:MAP Kinase Kinase Kinase 1; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases