Features characteristic to rheumatoid arthritis (RA) including synovial overgrowth and joint destruction are experimentally produced by augmenting c-fos gene expression. We show that cyclin dependent kinase inhibitor p21(waf1/cip1),, that inhibits cell proliferation, is down-regulated in conjunction with up-regulation of c-fos in the lymphocytes of patients with RA. As to the mechanism of down-regulation of p21(waf1/cip1) gene expression, transfection studies in U937 cells showed that c-fos down-regulated phosphorylation and dimerization of signal transducers and activators of transcription (STAT) 1, thereby inhibiting interferon gamma-induced transactivation of p21(waf1/cip1). Phosphorylation of STAT1 was indeed decreased in the lymphocytes of patients with RA. Thus, under overexpression of c-fos gene, c-Fos inactivates STAT1 to down-regulate p21(waf1/cip1) gene expression in the lymphocytes of patients with RA, and in this way may enhance proliferation of lymphocytes. (C) 2003 Elsevier Science (USA). All rights reserved.