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Mol Cell Biol, May 1998, p. 2462-2473, Vol. 18, No. 5
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
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


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.
Present address: Institute for Cellular Therpeutics, Allegheny
University of the Health Sciences, Philadelphia, PA 19102.
Present address: Dana Farber Cancer Institute, Boston, MA 02115.
§
Present address: Max-Delbrück-Center for Molecular Medicine,
13122 Berlin, Germany.
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