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Molecular and Cellular Biology, January 2003, p. 370-381, Vol. 23, No. 1
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.1.370-381.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Negative Feedback Regulation of MKK6 mRNA Stability by p38{alpha} Mitogen-Activated Protein Kinase

Concetta Ambrosino,1 Gaetane Mace,1 Stefanie Galban,2 Cornelius Fritsch,1,1 Kristina Vintersten,1 Emma Black,1 Myriam Gorospe,2 and Angel R. Nebreda1*

European Molecular Biology Laboratory, 69117 Heidelberg, Germany,1 Laboratory of Cellular and Molecular Biology, NIA-IRP, National Institutes of Health, Baltimore, Maryland 212242

Received 17 July 2002/ Returned for modification 4 September 2002/ Accepted 26 September 2002

p38 mitogen-activated protein (MAP) kinases play an important role in the regulation of cellular responses to all kinds of stresses. The most abundant and broadly expressed p38 MAP kinase is p38{alpha}, which can also control the proliferation, differentiation, and survival of several cell types. Here we show that the absence of p38{alpha} correlates with the up-regulation of one of its upstream activators, the MAP kinase kinase MKK6, in p38{alpha}-/- knockout mice and in cultured cells derived from them. In contrast, the expression levels of the p38 activators MKK3 and MKK4 are not affected in p38{alpha}-deficient cells. The increase in MKK6 protein concentration correlates with increased amounts of MKK6 mRNA in the p38{alpha}-/- cells. Pharmacological inhibition of p38{alpha} also up-regulates MKK6 mRNA levels in HEK293 cells. Conversely, reintroduction of p38{alpha} into p38{alpha}-/- cells reduces the levels of MKK6 protein and mRNA to the normal levels found in wild-type cells. Moreover, we show that the MKK6 mRNA is more stable in p38{alpha}-/- cells and that the 3'untranslated region of this mRNA can differentially regulate the stability of the lacZ reporter gene in a p38{alpha}-dependent manner. Our data indicate that p38{alpha} can negatively regulate the stability of the MKK6 mRNA and thus control the steady-state concentration of one of its upstream activators.

* Corresponding author. Mailing address: European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany. Phone: 49- 6221 387426. Fax: 49- 6221 387166. E-mail: nebreda{at}EMBL.de.

{dagger} Present address: German Cancer Research Center, 69120 Heidelberg, Germany.

Molecular and Cellular Biology, January 2003, p. 370-381, Vol. 23, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.1.370-381.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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