p38 Mitogen-activated protein kinase pathway suppresses cell survival by inducing dephosphorylation of mitogen-activated protein/extracellular signal-regulated kinase kinase1,2.
Raf/mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)1,2/extracellular signal-regulated kinase1,2 and MKK3,6/p38 mitogen-activated protein kinase pathways play an important role in cellular survival and apoptosis. The results of this study identify novel mechanisms to explain the opposing effects of these pathways in the regulation of apoptosis induction. Our results show that activation of p38 by adenoviral expression of MKK3b or arsenite treatment was followed by rapid dephosphorylation of MEK1,2 and subsequent apoptosis in human skin fibroblasts. Inhibition of p38 activity by SB203580 and adenoviral expression of dominant-negative forms of p38 potently inhibited MEK1,2 dephosphorylation and apoptosis. Strikingly, p38-mediated dephosphorylation of MEK1,2, was not detected in a series of transformed human cell lines. Taken together, we provide evidence for mechanisms unidentified previously that negatively regulates survival signaling during apoptosis induction. In addition, we show that in all transformed cell lines we have studied thus far, the function of this pathway is impaired.
Li
Song-Ping
SP
Turku Centre for Biotechnology, University of Turku, Finland.
Junttila
Melissa R
MR
Han
Jiahuai
J
Kähäri
Veli-Matti
VM
Westermarck
Jukka
J
D017209:Apoptosis; D018053:Arsenites / Q000494:pharmacology; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D006801:Humans; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D048371:MAP Kinase Kinase 3; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D012867:Skin / Q000166:cytology; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D018053:Arsenites; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D048371:MAP Kinase Kinase 3; C482125:MAP2K1 protein, human; C482530:MAP2K3 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C015001:arsenite