Ciliary neurotrophic factor and phorbol ester each decrease selected STAT3 pools in neuroblastoma cells by proteasome-dependent mechanisms.
Many cytokines and growth factors activate common signal transduction pathways and yet are able to elicit distinct cell-specific responses. We are defining mechanisms regulating signalling molecules in order to understand how cytokines can produce unique responses. It was found that individual members of the signal transducer and activator of transcription (STAT) family are regulated by ciliary neurotrophic factor (CNTF) and by protein kinase C. Treatment of SH-SY5Y human neuroblastoma cells with the phorbol ester, 12- O -tetradecanoylphorbol 13-acetate (TPA), for 4-5 h caused a 60% decline in both STAT2 and STAT3 levels and no decline in levels of STATs 1, 5 or 6, or in Jaks 1 or 2. The decline in STAT3 was inhibited by treatment with MG132, an inhibitor of proteasome-dependent protein degradation. Treatment of cells with CNTF induced a rapid tyrosine phosphorylation of STAT3 followed by a time-dependent decay of this signal. Loss of tyrosine phosphorylated STAT3 was inhibited by MG132 but did not require protein kinase C activity. These results suggest that STAT3 availability can be controlled by proteasome-dependent pathways activated either by protein kinase C or by cytokines.
Malek
R L
RL
Department of Biochemical Pharmacology, School of Pharmacy, State University of New York at Buffalo, Buffalo, NY 14260-1200, USA.
Halvorsen
S W
SW
D020934:Ciliary Neurotrophic Factor; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009447:Neuroblastoma / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D011493:Protein Kinase C / Q000378:metabolism; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D020934:Ciliary Neurotrophic Factor; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D004268:DNA-Binding Proteins; D007976:Leupeptins; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D011493:Protein Kinase C; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D013755:Tetradecanoylphorbol Acetate; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde