Affiliation:
1. Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, 1 and
2. University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 191042
Abstract
ABSTRACT
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 G
1
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 p21
WAF1
. Experiments addressing the potential mechanism of the apparent coordinate 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 deletion 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
WAF1
promoter, the first such repressor identified to date, and that sustained expression 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.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
107 articles.
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