Negative feedback regulation of MKK6 mRNA stability by p38alpha mitogen-activated protein kinase

Mol Cell Biol. 2003 Jan;23(1):370-81. doi: 10.1128/MCB.23.1.370-381.2003.


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 p38alpha, which can also control the proliferation, differentiation, and survival of several cell types. Here we show that the absence of p38alpha correlates with the up-regulation of one of its upstream activators, the MAP kinase kinase MKK6, in p38alpha(-/-) 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 p38alpha-deficient cells. The increase in MKK6 protein concentration correlates with increased amounts of MKK6 mRNA in the p38alpha(-/-) cells. Pharmacological inhibition of p38alpha also up-regulates MKK6 mRNA levels in HEK293 cells. Conversely, reintroduction of p38alpha into p38alpha(-/-) 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 p38alpha(-/-) cells and that the 3'untranslated region of this mRNA can differentially regulate the stability of the lacZ reporter gene in a p38alpha-dependent manner. Our data indicate that p38alpha can negatively regulate the stability of the MKK6 mRNA and thus control the steady-state concentration of one of its upstream activators.

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Base Sequence
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cells, Cultured
  • Cycloheximide / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Feedback, Physiological*
  • Gene Expression Regulation
  • Imidazoles / pharmacology
  • MAP Kinase Kinase 3
  • MAP Kinase Kinase 4*
  • MAP Kinase Kinase 6
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism*
  • Molecular Sequence Data
  • Myocytes, Cardiac / metabolism
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Pyridines / pharmacology
  • RNA Stability*
  • RNA, Messenger / metabolism
  • Up-Regulation
  • p38 Mitogen-Activated Protein Kinases


  • 3' Untranslated Regions
  • Enzyme Inhibitors
  • Imidazoles
  • Pyridines
  • RNA, Messenger
  • Cycloheximide
  • Protein-Tyrosine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 3
  • MAP Kinase Kinase 4
  • MAP Kinase Kinase 6
  • Map2k3 protein, mouse
  • Map2k4 protein, mouse
  • Map2k6 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases
  • SB 203580