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J. Biol. Chem., Vol. 277, Issue 48, 46799-46808, November 29, 2002
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From the Department of Biochemistry, McMaster University, Hamilton,
Ontario L8N 3Z5, Canada
Human host cell factor-1 (HCF-1) is essential for
cell cycle progression and is required, in conjunction with the herpes
simplex virus transactivator VP16, for induction of viral
immediate-early gene expression. We show here that HCF-1 directly binds
to the Myc-interacting protein Miz-1, a transcription factor that
induces cell cycle arrest at G1, in part by directly
stimulating expression of the cyclin-dependent kinase
inhibitor p15INK4b. A domain encompassing amino acids
750-836, contained within a subregion of HCF-1 required for cell cycle
progression, was sufficient to bind Miz-1. Conversely, HCF-1 interacted
with two separate regions in Miz-1: the N-terminal POZ domain and a
C-terminal domain (residues 637-803) previously shown to harbor
determinants for interaction with c-Myc and the coactivator p300. The
latter functioned as a potent transactivation domain when tethered to DNA, indicating that HCF-1 targets a transactivation function in Miz-1.
HCF-1 or a Miz-1-binding fragment of HCF-1 repressed transactivation by
Gal4-Miz-1 in transfection assays. Moreover, HCF-1 repressed
Miz-1-mediated transactivation of a reporter gene linked to the
p15INK4b promoter. Protein/protein interaction studies and
transient transfection assays demonstrated that HCF-1 interferes with
recruitment of p300 to Miz-1, similar to what has been reported with
c-Myc. Our findings identify Miz-1 as a novel HCF-1-interacting partner
and illustrate cross-talk between these two proteins that may be of consequence to their respective functions in gene regulation and their
opposing effects on the cell cycle.
Host Cell Factor-1 Interacts with and Antagonizes Transactivation
by the Cell Cycle Regulatory Factor Miz-1*
,
*
This work was supported in part by the National Cancer
Institute of Canada.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of Natural Science and Engineering Research Council of
Canada graduate studentship.
§
To whom correspondence should be addressed: Dept. of Biochemistry,
Faculty of Health Sciences, McMaster University, 1200 Main St. W.,
Hamilton, Ontario L8N 3Z5, Canada. Tel.: 905-525-9140 (ext. 22184);
Fax: 905-546-0800; E-mail: caponej@mcmaster.ca.
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