Negative Feedback Regulation of MKK6 mRNA Stability by p38α Mitogen-Activated Protein Kinase

Abstract

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 p38α, which can also control the proliferation, differentiation, and survival of several cell types. Here we show that the absence of p38α correlates with the up-regulation of one of its upstream activators, the MAP kinase kinase MKK6, in p38α^−/− 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 p38α-deficient cells. The increase in MKK6 protein concentration correlates with increased amounts of MKK6 mRNA in the p38α^−/− cells. Pharmacological inhibition of p38α also up-regulates MKK6 mRNA levels in HEK293 cells. Conversely, reintroduction of p38α into p38α^−/− 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 p38α^−/− cells and that the 3′untranslated region of this mRNA can differentially regulate the stability of the lacZ reporter gene in a p38α-dependent manner. Our data indicate that p38α can negatively regulate the stability of the MKK6 mRNA and thus control the steady-state concentration of one of its upstream activators.

ACKNOWLEDGMENTS

We thank Juan Valcarcel for many useful suggestions and for critical reading of the manuscript. We are also grateful to Almudena Porras and Margaret Jones for their help during the early stages of this work and to Stefania Castagnetti for technical advice.