Ciliary neurotrophic factor and phorbol ester each decrease selected STAT3pools in neuroblastoma cells by proteasome-dependent mechanisms

Many cytokines and growth factors activate common signal transduction pathw ays and let are able to elicit distinct cell-specific responses. We are def ining mechanisms regulating signalling molecules in order to understand how cytokines can produce unique responses. It was found that individual membe rs of the signal transducer and activator of transcription (STAT) family ar e 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 b oth ST.-ln and STAT3 levels and no decline in levels of STATs 1, 5 or 6, or in Jaks I or 2, The decline in STAT3 was inhibited by treatment with MG132 , an inhibitor of proteasome-dependent protein degradation. Treatment of ce lls with CNTF induced a rapid tyrosine phosphorylation of STAT3 followed ba a time-dependent decay of this signal. Loss of tyrosine phosphorylated STA T3,vas inhibited by MG132 but did not require protein kinase C activity. Th ese results suggest that STAT3 availability can be controlled by proteasome -dependent pathways activated either by protein kinase C or by cytokines. ( C) 1999 Academic Press.