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Vol. 15, Issue 2, 922-933, February 2004
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Mitogen-activated Protein Kinase Sensitizes Cells to Apoptosis Induced by Different Stimuli
* Departamento de Bioquimica y Biologia Molecular II (Centro Mixto UCM/CSIC), UCM, Ciudad Universitaria, 28040 Madrid, Spain;
|| Centro de Citometría de Flujo y Microscopía Confocal, Facultad de Farmacia, UCM, Ciudad Universitaria, 28040 Madrid, Spain; and
European Molecular Biology Laboratory, 69117 Heidelberg, Germany
Submitted August 14, 2003;
Accepted October 26, 2003
Monitoring Editor: Carl-Henrik Heldin
p38
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 knockout mice to study the role of this signaling pathway in the regulation of apoptosis. Here, we show that cardiomyocytes and fibroblasts lacking p38 are more resistant to apoptosis induced by different stimuli. The reduced apoptosis of p38-deficient cells correlates with decreased expression of the mitochondrial proapoptotic protein Bax and the apoptosis-inducing receptor Fas/CD-95. Cells lacking p38 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. 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-/- cells. Thus, p38 seems to sensitize cells to apoptosis via both up-regulation of proapoptotic proteins and down-regulation of survival pathways.
Equally contributed to the experimental work.
¶ Present address: Unidad de Citometría, Centro Nacional de Investigaciones Cardiovasculares, Instituto de Salud Carlos III, Ronda de Poniente 5, Tres Cantos 28760 Madrid, Spain.
Corresponding authors. E-mail addresses: maporras{at}farm.ucm.es or nebreda{at}EMBL-Heidelberg.de.
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