Functional interaction of STAT3 transcription factor with the cell cycle inhibitor p21(WAF1/CIP1/SD11)

Signal transducers and activators of transcription (STAT) factors are cytop lasmic proteins that induce gene activation in response to cytokine recepto r stimulation, Following tyrosine phosphorylation, STAT proteins dimerize, translocate into the nucleus, and activate specific target genes. Activatio n is transient, and down-regulation of STAT signaling occurs within a few h ours. In the present study, we show that the cyclin-dependent kinase inhibi tor p21(WAF1/CIP1/SD11) inhibits STAT3 transcriptional activation. Followin g leukemia inhibitory factor stimulation, p21(WAF1/CIP1/SD11) was found to associate with STAT3 proteins in coimmunoprecipitation and pull down assays . In vivo, overexpression of p21(WAF1/CIP1/SD11) reduced transcriptional ac tivation by STAT3 proteins but did not modify DNA binding activity. Interes tingly, pull down experiments showed that p21(WAF1/CIP1/SD11) could interac t with the CREB-binding coactivator protein, and inhibition of STAT3 activi ty by p21(WAF1/CIP1/SD11) did not occur when CREB-binding protein was overe xpressed, These results suggest a model by which p21(WAF1/CIP1/SD11) functi ons as an inhibitor of STAT3 signaling and highlight a new activity for thi s cyclin-dependent kinase inhibitor.