Abstract
STAT3 transcription factors are cytoplasmic proteins that induce gene activation in response to cytokine receptor stimulation. Following tyrosine phosphorylation, STAT3 proteins dimerize, translocate into the nucleus, and activate specific target genes. Activation is transient, and down-regulation of STAT3 signaling occurs within a few hours. In this study, we show that cyclin D1 inhibits STAT3 activation. In co-immunoprecipitation and pull-down assays, cyclin D1 was found to associate with the activation domain of STAT3 upon interleukin-6 stimulation. Overexpression of cyclin D1 inhibited transcriptional activation by STAT3 proteins. This effect was not shared by cyclin E, was independent of association with Cdk4, and was unaffected by inhibitors 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 nuclear 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 activity and highlight a new activity for this cell cycle regulatory protein.
Highlights
IntroductionCyclin D1 can activate estrogen receptor transcription through a direct interaction with the ligand-binding domain of the receptor [20, 21]
Following IL-6 stimulation, nuclear extracts were recovered from HepG2 hepatoma cells, and co-immunoprecipitations were performed alternatively with polyclonal antibodies directed against cyclin D1 (Fig. 1A, lane 2), polyclonal antibodies directed against STAT3, or nonspecific antibodies
The results presented in this study describe a new pathway for inhibiting STAT3 activation and establish a new role for cyclin D1 as a STAT3 inhibitor
Summary
Cyclin D1 can activate estrogen receptor transcription through a direct interaction with the ligand-binding domain of the receptor [20, 21] This effect is independent of Cdk and is explained by the recruitment of the SRC1a family of coactivators by cyclin D1 [22]. Cyclin D1 has been shown to repress muscle differentiation and MyoD-mediated transcription in part through an Rb-independent mechanism [26, 27] Taken together, these studies establish a new Cdk-independent role of cyclin D1 as a transcriptional regulator [19]. Stimulation, cyclin D1 interacts with STAT3 and inhibits its transcriptional activity This effect is not shared by cyclin E, is independent of Cdk, and is related to reduced STAT3 nuclear expression in HepG2 cells. These results reveal an unexpected relationship between cyclin D1 and STAT3 proteins and led us to propose that cyclin D1 is part of a feedback network controlling the down-regulation of STAT3 activity
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