Functional Interaction of STAT3 Transcription Factor with the Cell Cycle Inhibitor p21

Signal transducers and activators of transcription (STAT) factors are cytoplasmic proteins that induce gene activation in response to cytokine receptor stimulation. Following tyrosine phosphorylation, STAT proteins dimerize, translocate into the nucleus, and activate specific target genes. Activation is transient, and down-regulation of STAT signaling occurs within a few hours. In the present study, we show that the cyclin-dependent kinase inhibitor p21(WAF1/CIP1/SDI1) inhibits STAT3 transcriptional activation. Following leukemia inhibitory factor stimulation, p21(WAF1/CIP1/SDI1) was found to associate with STAT3 proteins in coimmunoprecipitation and pull down assays. In vivo, overexpression of p21(WAF1/CIP1/SDI1) reduced transcriptional activation by STAT3 proteins but did not modify DNA binding activity. Interestingly, pull down experiments showed that p21(WAF1/CIP1/SDI1) could interact with the CREB-binding coactivator protein, and inhibition of STAT3 activity by p21(WAF1/CIP1/SDI1) did not occur when CREB-binding protein was overexpressed. These results suggest a model by which p21(WAF1/CIP1/SDI1) functions as an inhibitor of STAT3 signaling and highlight a new activity for this cyclin-dependent kinase inhibitor.