Krox-20 inhibits Jun-NH2-terminal kinase/c-Jun to control Schwann cell proliferation and death

J Cell Biol. 2004 Feb 2;164(3):385-94. doi: 10.1083/jcb.200307132.

Abstract

The transcription factor Krox-20 controls Schwann cell myelination. Schwann cells in Krox-20 null mice fail to myelinate, and unlike myelinating Schwann cells, continue to proliferate and are susceptible to death. We find that enforced Krox-20 expression in Schwann cells cell-autonomously inactivates the proliferative response of Schwann cells to the major axonal mitogen beta-neuregulin-1 and the death response to TGFbeta or serum deprivation. Even in 3T3 fibroblasts, Krox-20 not only blocks proliferation and death but also activates the myelin genes periaxin and protein zero, showing properties in common with master regulatory genes in other cell types. Significantly, a major function of Krox-20 is to suppress the c-Jun NH2-terminal protein kinase (JNK)-c-Jun pathway, activation of which is required for both proliferation and death. Thus, Krox-20 can coordinately control suppression of mitogenic and death responses. Krox-20 also up-regulates the scaffold protein JNK-interacting protein 1 (JIP-1). We propose this as a possible component of the mechanism by which Krox-20 regulates JNK activity during Schwann cell development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Animals, Newborn
  • Apoptosis / physiology*
  • Carrier Proteins / metabolism
  • Cell Division / physiology*
  • Cell Survival
  • DNA / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Down-Regulation
  • Early Growth Response Protein 2
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 7
  • MAP Kinase Kinase Kinase 1*
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Myelin Sheath / genetics
  • Myelin Sheath / metabolism
  • Nerve Tissue Proteins / metabolism
  • Neuregulin-1
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Rats
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Schwann Cells / cytology
  • Schwann Cells / physiology*
  • Sciatic Nerve / cytology
  • Sciatic Nerve / growth & development
  • Signal Transduction / physiology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA-Binding Proteins
  • Early Growth Response Protein 2
  • Egr2 protein, mouse
  • Egr2 protein, rat
  • MAPK8IP1 protein, human
  • Mapk8ip protein, mouse
  • Mapk8ip1 protein, rat
  • Nerve Tissue Proteins
  • Neuregulin-1
  • Nrg1 protein, mouse
  • Nrg1 protein, rat
  • Proto-Oncogene Proteins c-jun
  • Recombinant Fusion Proteins
  • Transcription Factors
  • Transforming Growth Factor beta
  • DNA
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 1
  • MAP Kinase Kinase Kinases
  • MAP3K1 protein, human
  • Map3k1 protein, mouse
  • MAP Kinase Kinase 7
  • MAP2K7 protein, human
  • Map2k7 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases