In response to certain cytokines, signal transducer and activator of transcription (STAT) 3 protein undergoes tyrosine phosphorylation, dimerizes, translocates to the nucleus, and promotes specific gene expression. However, the mechanisms involved in the attenuation of such STAT signaling are not as clear. Bienvenu et al. have found that cyclin D1, independent of cyclin-dependent kinase 4 (Cdk4) activity, can inhibit STAT3-mediated signaling. Endogenous cyclin D1 associated with STAT3 in cells treated for 2 hours after treatment with interleukin 6 (IL-6), an activator of STAT3. Overexpression of cyclin D1 reduced STAT3-dependent gene expression in a dose-dependent manner. Although cyclin D1 had no effect on STAT3 DNA binding, cyclin D1 did bind to the transcriptional activation domain of STAT3, suggesting a mechanism whereby STAT3-dependent transcription could be immediately attenuated. Additionally, in the presence of cyclin D1 the amount of STAT3 in the nucleus was decreased, providing a possible second mechanism whereby cyclin D1 shuttles STAT3 out of the nucleus to provide longer-term inhibition of STAT3-mediated signaling. F. Bienvenu, H. Gascan, O. Coqueret, Cyclin D1 represses STAT3 activation through a Cdk4-independent mechanism. J. Biol. Chem. 276 , 16840-16847 (2001). [Abstract] [Full Text]