TYPE-I INTERFERON INDUCTION OF THE CDK-INHIBITOR P21(WAF1) IS ACCOMPANIED BY ORDERED G1 ARREST, DIFFERENTIATION AND APOPTOSIS OF THE DAUDI B-CELL LINE

We show, in this study, that type I IFN induction of the cyclin-depend ent kinase (cdk) inhibitor p21(WAF1) in the human Burkitt lymphoma B c ell-line Daudi and ensuing cell cycle arrest correlate with the termin al differentiation of these cells, and is ultimately followed by apopt osis and cell death. The expression of p21(WAF1) paralleled the onset of G1 arrest and the reduction of surface IgM expression which was use d as a marker of the differentiation response, and the IFN treated cel ls acquired a typical plasma cell-like morphology. The type II IFN IFN gamma, which does not inhibit the growth of Daudi cells, did not indu ce the expression of p21(WAF1), nor affect the expression of surface I gM. The induction of p21(WAF1) which paralleled the inhibition of the phosphorylation of the retinoblastoma protein, pRB, was preceded by th e strong reduction in c-myc levels, We propose that the coupled down-r egulation of c-myc and induction of p21(WAF1) may be crucial to the in duction of differentiation and G1 arrest in Daudi cells by type I IFN. Growth arrest and differentiation was followed by apoptosis and cell death, and was accompanied by the induction of the activity of the apo ptotic ICE-family protease CPP32. G1 arrest and differentiation follow ed by apoptotic cell death are characteristics of terminal differentia tion. Thus, our data suggest that the induction of p21(WAF1) and G1 ar rest mediated by type I IFN in Daudi cells is part of terminal differe ntiation response in these cells, highlighting a role for type I IFN a s B cell terminal differentiation factors.