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J. Biol. Chem., Vol. 277, Issue 41, 38755-38763, October 11, 2002
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From the Posttranslational modifications may alter the
biochemical functions of a protein by modifying associations with other
macromolecules, allosterically altering intrinsic catalytic activities,
or determining subcellular localization. The adenovirus-transforming
protein E1A is acetylated by its cellular targets, the co-activators
CREB-binding protein, p300, and p300/CREB-binding protein-associated
factor in vitro and also in vivo at a
single lysine residue (Lys239) within a multifunctional
carboxyl-terminal domain necessary for both nuclear localization and
interaction with the transcriptional co-repressor carboxyl-terminal
binding protein (CtBP). In contrast to a previous report, we
demonstrate that acetylation of Lys239 does not disrupt
CtBP binding and that 12 S E1A-mediated repression of CREB-binding
protein-dependent transcription does not require recruitment of
CtBP. Instead we find that the cytoplasmic fraction of E1-transformed
293 cells is enriched for acetylated E1A with relative exclusion from
the nuclear compartment. Whereas wild type 12 S E1A binds
importin-
Acetylation of the Adenovirus-transforming Protein E1A Determines
Nuclear Localization by Disrupting Association with Importin-
*
,
, and**
Division of Molecular Medicine, Department
of Medicine, and Department of Biochemistry and Molecular Biology,
Oregon Health and Science University, Portland, Oregon 97201, the
§ Department of Molecular Microbiology and Immunology,
St. Louis University, St. Louis, Missouri 63104, and the
¶ Departments of Obstetrics and Gynecology and of Biological
Chemistry, University of Michigan, Ann Arbor, Michigan 48109
3, binding affinity was markedly reduced both by single
amino acid substitution mutations and acetylation at
Lys239. This is the first demonstration that acetylation
may alter nuclear partitioning by direct interference with nuclear
import receptor recognition. The finding that the cytoplasmic fraction
of E1A is acetylated indicates that E1A may exert its pleiotropic
effects on cellular transformation in part by affecting cytoplasmic processes.
*
This work was supported by funding from an American Cancer
Society Research Grant (to R. P. S. K.) and by NIDDK, National Institutes of Health, Public Health Service Grants DK051732 and DK060133 (to J. R. L).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.
These authors contributed equally to this work.
**
Scholar of the Mallinckrodt Foundation. To whom correspondence
should be addressed: Division of Molecular Medicine, HRC-3, Oregon
Health & Science University, 3181 S.W. Sam Jackson Park Rd., Portland,
OR 97201. Tel.: 503-494-4392; Fax: 503-494-7368; E-mail:
lundblad@ohsu.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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