THE GFI-1B PROTO-ONCOPROTEIN REPRESSES P21(WAF1) AND INHIBITS MYELOIDCELL-DIFFERENTIATION

Gfi-1 is a cellular proto oncogene that was identified as a target of provirus integration in T-cell lymphoma lines selected for interleukin -2 (IL-2) independence in culture and in primary retrovirus-induced ly mphomas. Gfi-1 encodes a zinc finger protein that functions as a trans criptional repressor. Here we show that Gfi-1B, a Gfi-1 related gene e xpressed in bone marrow and spleen, also encodes a transcriptional rep ressor. IL-6-induced G(1) arrest and differentiation of the myelomonoc ytic cell line M1 were linked to the downregulation of Gfi-1B and the parallel induction of the cyclin-dependent kinase inhibitor p21(WAF1). Experiments addressing the potential mechanism of the apparent coordi nate regulation of these genes revealed that Gfi-1B represses p21(WAF1 ) directly by binding to a high-affinity site at -1518 to -1530 in the p21(WAF1) promoter. Forced expression of Gfi-1B, but not of Gfi-1B de letion mutants lacking the repressor domain, blocked the IL-6-mediated induction of p21(WAF1) and inhibited G(1) arrest and differentiation. We conclude that Gfi-1B is a direct repressor of the p21 promoter, th e first such repressor identified to date, and that sustained expressi on of Gfi-1B blocks IL-6-induced G(1) arrest and differentiation of M1 cells perhaps because it prevents p21(WAF1) induction by IL-6.