Cyclin D1 represses STAT3 activation through a Cdk4-independent mechanism

STAT3 transcription factors are cytoplasmic proteins that induce gene activ ation in response to cytokine receptor stimulation. Following tyrosine phos phorylation, STAT3 proteins dimerize, translocate into the nucleus, and act ivate specific target genes. Activation is transient, and down-regulation o f STAT3 signaling occurs within a few hours. In this study, we show that cy clin D1 inhibits STAT3 activation. In co-immunoprecipitation and pull-down assays, cyclin D1 was found to associate with the activation domain of STAT 3 upon interleukin-6 stimulation. Overexpression of cyclin D1 inhibited tra nscriptional activation by STAT3 proteins. This effect was not shared by cy clin E, was independent of association with Cdk4, and was unaffected by inh ibitors of Cdk4, Whereas cyclin D1 had no effect on the steady-state level of STAT3 proteins in the cytoplasm, it was found to reduce the STAT3 nuclea r level in HepG2 cells. These results suggest a model by which cyclin D1 is part of a feedback network controlling the down-regulation of STAT3 activi ty and highlight a new activity for this cell cycle regulatory protein.