MEKK1 mediates the ubiquitination and degradation of c-Jun in response to osmotic stress.
c-Jun, a major transcription factor in the activating protein 1 family of regulatory proteins, is activated by many physiologic and pathological stimuli. We show here that c-Jun was downregulated in response to osmotic stress via ubiquitination-dependent degradation by the PHD/RING finger domain of MEKK1, which exhibited E3 ubiquitin ligase activity toward c-Jun in vitro and in vivo. The reduced c-Jun protein level resulting from exogenous expression of wild-type MEKK1 and the opposite effect induced by expression of a MEKK1 PHD/RING finger domain mutant were consistent with a higher level of c-Jun protein in MEKK1(-/-) cells than in corresponding wild-type cells. The deficiency of MEKK1 blocked posttranslational downregulation of c-Jun in response to osmotic stress. Furthermore, apoptosis induced by osmotic stress was suppressed by overexpression of c-Jun, indicating that the downregulation of c-Jun promotes apoptosis.
Xia
Yan
Y
Department of Neuro-Oncology, Unit 1002, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Wang
Ji
J
Xu
Shuichan
S
Johnson
Gary L
GL
Hunter
Tony
T
Lu
Zhimin
Z
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D009154:Mutation; D009997:Osmotic Pressure; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D017434:Protein Structure, Tertiary; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D016755:Proto-Oncogene Proteins c-jun; D044767:Ubiquitin-Protein Ligases; D048055:Mitogen-Activated Protein Kinase 8; D048728:MAP Kinase Kinase Kinase 1; D046988:Proteasome Endopeptidase Complex