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Endocrinology Vol. 141, No. 12 4383-4395
Copyright © 2000 by The Endocrine Society

ARTICLES

p38 Mitogen-Activated Protein Kinase Mediates Tumor Necrosis Factor-{alpha}-Induced Apoptosis in Rat Fetal Brown Adipocytes1

Amparo Valladares2, Alberto M. Álvarez, Juan José Ventura2, Cesar Roncero, Manuel Benito and Almudena Porras

Departamento de Bioquímica y Biología Molecular II, Instituto de Bioquímica, Centro Mixto del Consejo Superior de Investigaciones Científicas y de la Universidad Complutense de Madrid (A.V., J.J.V., C.R., M.B., A.P.); Centro de Citometría de Flujo y Microscopía Confocal, Universidad Complutense de Madrid (A.M.A.); Facultad de Farmacia, Universidad Complutense, Ciudad Universitaria, 28040 Madrid, Spain

Address all correspondence and requests for reprints to: Dr. Almudena Porras, Departamento de Bioquímica y Biología Molecular II, Instituto de Bioquímica, Centro Mixto del Consejo Superior de Investigaciones Científicas y de la Universidad Complutense de Madrid, Facultad de Farmacia, 28040 Madrid, Spain.

Tumor necrosis factor-{alpha} (TNF{alpha}) induces apoptosis and cell growth inhibition in primary rat fetal brown adipocytes. Here, we examine the role played by some members of the mitogen-activated protein kinase (MAPK) superfamily. TNF{alpha} activates extracellular regulated kinase-1/2 (ERK1/2) and p38MAPK. Inhibition of p38MAPK by either SB203580 or SB202190 highly reduces apoptosis induced by TNF{alpha}, whereas ERK inhibition potentiates it. Moreover, cotransfection of an active MKK3 mutant and p38MAPK induces apoptosis. p38MAPK inhibition also prevents TNF{alpha}-induced cell cycle arrest, whereas MEK1 inhibition enhances this effect, which correlates with changes in proliferating cell nuclear antigen expression, but not in cyclin D1.

c-Jun and activating transcription factor-1 are potential downstream effectors of p38MAPK and ERKs upon TNF{alpha} treatment. Thus, TNF{alpha}-induced c-Jun messenger RNA expression requires ERKs activation, whereas p38MAPK inhibition enhances its expression. In addition, TNF{alpha}-induced activating transcription factor-1 phosphorylation is extensively decreased by SB203580. However, TNF{alpha}- induced NF-{kappa}B DNA-binding activity is independent of p38MAPK and ERK activation. On the other hand, C/EBP homology protein does not appear to mediate the actions of TNF{alpha}, because its expression is almost undetectable and even reduced by TNF{alpha}.

Finally, although TNF{alpha} induces c-Jun N-terminal kinase (JNK) activation, transfection of a dominant negative of either JNK1 or JNK2 had no effect on TNF{alpha}-induced apoptosis. These results suggest that p38MAPK mediates TNF{alpha}-induced apoptosis and cell cycle arrest, whereas ERKs do the opposite, and JNKs play no role in this process of apoptosis.




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