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Mol Cell Biol, May 1998, p. 2462-2473, Vol. 18, No. 5
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Gfi-1B Proto-Oncoprotein Represses p21WAF1 and Inhibits Myeloid Cell Differentiation

Betty Tong,1,dagger H. Leighton Grimes,1,Dagger Tong-Yuan Yang,1 Susan E. Bear,1 Zhihai Qin,1,§ Keyong Du,2 Wafik S. El-Deiry,2 and Philip N. Tsichlis1,*

Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111,1 and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 191042

Received 23 September 1997/Returned for modification 30 October 1997/Accepted 1 February 1998

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 lymphomas. Gfi-1 encodes a zinc finger protein that functions as a transcriptional repressor. Here we show that Gfi-1B, a Gfi-1 related gene expressed in bone marrow and spleen, also encodes a transcriptional repressor. IL-6-induced G1 arrest and differentiation of the myelomonocytic cell line M1 were linked to the downregulation of Gfi-1B and the parallel induction of the cyclin-dependent kinase inhibitor p21WAF1. Experiments addressing the potential mechanism of the apparent coordinate regulation of these genes revealed that Gfi-1B represses p21WAF1 directly by binding to a high-affinity site at -1518 to -1530 in the p21WAF1 promoter. Forced expression of Gfi-1B, but not of Gfi-1B deletion mutants lacking the repressor domain, blocked the IL-6-mediated induction of p21WAF1 and inhibited G1 arrest and differentiation. We conclude that Gfi-1B is a direct repressor of the p21WAF1 promoter, the first such repressor identified to date, and that sustained expression of Gfi-1B blocks IL-6-induced G1 arrest and differentiation of M1 cells perhaps because it prevents p21WAF1 induction by IL-6.

* Corresponding author. Mailing address: Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111. Phone: (215) 728-3635. Fax: (215) 728-2741. E-mail: tsichlis{at}archimedes.rm.fccc.edu.

dagger Present address: Institute for Cellular Therpeutics, Allegheny University of the Health Sciences, Philadelphia, PA 19102.

Dagger Present address: Dana Farber Cancer Institute, Boston, MA 02115.

§ Present address: Max-Delbrück-Center for Molecular Medicine, 13122 Berlin, Germany.

Mol Cell Biol, May 1998, p. 2462-2473, Vol. 18, No. 5
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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