SOCS3 suppresses AP-1 transcriptional activity in neuroblastoma cells through inhibition of c-Jun N-terminal kinase.
Transduction and activation of an inducible form of STAT3 (signal transducer and activator of transcription) sufficed to increase VIP (vasoactive intestinal protein) mRNA concentrations in neuroblastoma cells. Overexpression of SOCS3 (suppressor of cytokine signaling) inhibited and mutant SOCS3 (with an inactivating point mutation in amino acid 25) enhanced the induction of VIP mRNA by CNTF (ciliary neurotrophic factor). Because mutant SOCS3 did not augment the increase in STAT transcriptional activity following CNTF stimulation, the enhancement by mutant SOCS3 of the actions of CNTF cannot be attributed to changes in STAT3 signaling. Mutant SOCS3 increased AP-1 (activator protein) transcriptional activity and JNK (c-Jun N-terminal kinase) activity and SOCS3 bound to the scaffolding protein, JNK-interacting protein-1: these observations provide a plausible explanation for the enhancement by mutant SOCS3 of the actions of CNTF. We conclude that endogenous SOCS3 inhibits AP-1 activity through blocking of JNK phosphorylation.
Centre for Neuroscience, Queen Mary's School of Medicine, University of London, E1 2AT, London, UK.
Tizong
T
Miao
Dongsheng
D
Wu
Yi
Y
Zhang
Xuenong
X
Bo
Fang
F
Xiao
Xinyu
X
Zhang
Charalambos
C
Magoulas
Maria Cristina
MC
Subang
Ping
P
Wang
Peter M
PM
Richardson
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D015536:Down-Regulation / Q000235:genetics; D025461:Feedback, Physiological / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009447:Neuroblastoma; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*; D014660:Vasoactive Intestinal Peptide / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D020934:Ciliary Neurotrophic Factor; C490666:MAPK8IP1 protein, human; D012333:RNA, Messenger; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D018808:Transcription Factor AP-1; D014660:Vasoactive Intestinal Peptide; D048031:JNK Mitogen-Activated Protein Kinases