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Molecular and Cellular Biology, June 1999, p. 4390-4404, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Btf, a Novel Death-Promoting Transcriptional
Repressor That Interacts with Bcl-2-Related Proteins
Gary M.
Kasof,1
Lakshmi
Goyal,1 and
Eileen
White1,2,3,4,*
Center for Advanced Biotechnology and
Medicine,1 Howard Hughes Medical
Institute,2 Department of Molecular
Biology and Biochemistry,3 and Cancer
Institute of New Jersey,4 Rutgers
University, Piscataway, New Jersey 08854
Received 3 September 1998/Returned for modification 29 October
1998/Accepted 26 February 1999
The adenovirus E1B 19,000-molecular-weight (19K) protein is a
potent inhibitor of apoptosis and cooperates with E1A to transform primary rodent cells. E1B 19K shows sequence and functional homology to
the mammalian antiapoptotic gene product, Bcl-2. Like Bcl-2, the
biochemical mechanism of E1B 19K function includes binding to and
antagonization of cellular proapoptotic proteins such as Bax, Bak, and
Nbk/Bik. In addition, there is evidence that E1B 19K can affect gene
expression, but whether this contributes to its antiapoptotic function
has not been determined. In an effort to further understand the
functions of E1B 19K, we screened for 19K-associated proteins by the
yeast two-hybrid system. A novel protein, Btf (Bcl-2-associated
transcription factor), that interacts with E1B 19K as well as with the
antiapoptotic family members Bcl-2 and Bcl-xL but not with
the proapoptotic protein Bax was identified. btf is a
widely expressed gene that encodes a protein with homology to the basic
zipper (bZip) and Myb DNA binding domains. Btf binds DNA in vitro and
represses transcription in reporter assays. E1B 19K, Bcl-2, and
Bcl-xL sequester Btf in the cytoplasm and block its
transcriptional repression activity. Expression of Btf also inhibited
transformation by E1A with either E1B 19K or mutant p53, suggesting a
role in either promotion of apoptosis or cell cycle arrest. Indeed, the
sustained overexpression of Btf in HeLa cells induced apoptosis, which
was inhibited by E1B 19K. Furthermore, the chromosomal localization of
btf (6q22-23) maps to a region that is deleted in some
cancers, consistent with a role for Btf in tumor suppression. Thus,
btf may represent a novel tumor suppressor gene residing in
a unique pathway by which the Bcl-2 family can regulate apoptosis.
*
Corresponding author. Mailing address: Howard Hughes
Medical Institute, Center for Advanced Biotechnology and Medicine, 679 Hoes Ln., Piscataway, NJ 08854. Phone: (732) 235-5329. Fax: (732) 235-5795. E-mail: ewhite{at}mbcl.rutgers.edu.
Molecular and Cellular Biology, June 1999, p. 4390-4404, Vol. 19, No. 6
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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