Krox-20 inhibits Jun-NH2-terminal kinase/c-Jun to control Schwann cell proliferation and death.
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.
Parkinson
David B
DB
Department of Anatomy and Developmental Biology, University College London, Gower Street, London, WC1E 6BT UK. david.parkinson@ucl.ac.uk
Bhaskaran
Ambily
A
Droggiti
Anna
A
Dickinson
Sarah
S
D'Antonio
Maurizio
M
Mirsky
Rhona
R
Jessen
Kristjan R
KR
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division / Q000502:physiology*; D002470:Cell Survival; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D051767:Early Growth Response Protein 2; D048031:JNK Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020890:Neuregulin-1; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012583:Schwann Cells / Q000166:cytology / Q000502:physiology*; D012584:Sciatic Nerve / Q000166:cytology / Q000254:growth & development; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; C497328:Egr2 protein, rat; C490666:MAPK8IP1 protein, human; C490665:Mapk8ip protein, mouse; C110528:Mapk8ip1 protein, rat; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; C490580:Nrg1 protein, rat; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D004247:DNA; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; C482576:MAP3K1 protein, human; C482578:Map3k1 protein, mouse; D048688:MAP Kinase Kinase 7; C482569:MAP2K7 protein, human; C482570:Map2k7 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases