P38 alpha mitogen-activated protein kinase sensitizes cells to apoptosis induced by different stimuli.
p38 alpha mitogen-activated protein (MAP) kinase is a broadly expressed signaling molecule that participates in the regulation of cellular responses to stress as well as in the control of proliferation and survival of many cell types. We have used cell lines derived from p38 alpha knockout mice to study the role of this signaling pathway in the regulation of apoptosis. Here, we show that cardiomyocytes and fibroblasts lacking p38 alpha are more resistant to apoptosis induced by different stimuli. The reduced apoptosis of p38 alpha-deficient cells correlates with decreased expression of the mitochondrial proapoptotic protein Bax and the apoptosis-inducing receptor Fas/CD-95. Cells lacking p38 alpha also have increased extracellular signal-regulated kinase (ERKs) MAP kinase activity, and the up-regulation of this survival pathway seems to be at least partially responsible for the reduced levels of apoptosis in the absence of p38 alpha. Phosphorylation of the transcription factor STAT3 on Ser-727, mediated by the extracellular signal-regulated kinase MAP kinase pathway, may contribute to the decrease in both Bax and Fas expression in p38 alpha-/- cells. Thus, p38 alpha seems to sensitize cells to apoptosis via both up-regulation of proapoptotic proteins and down-regulation of survival pathways.
Porras
Almudena
A
Departamento de Bioquimica y Biologia Molecular II, Centro Mixto UCM/CSIC, UCM, Ciudad Universitaria, 28040 Madrid, Spain. maporras@farm.ucm.es
Zuluaga
Susana
S
Black
Emma
E
Valladares
Amparo
A
Alvarez
Alberto M
AM
Ambrosino
Concetta
C
Benito
Manuel
M
Nebreda
Angel R
AR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000494:pharmacology
C494827:Bax protein, mouse; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D048308:Mitogen-Activated Protein Kinase 14; D020928:Mitogen-Activated Protein Kinases