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J. Biol. Chem., Vol. 277, Issue 37, 34471-34479, September 13, 2002
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From the Department of Epidermal keratinocyte differentiation is
accompanied by differential regulation of E2F genes,
including up-regulation of E2F-5 and its concomitant association with
the retinoblastoma family protein p130. This complex appears to play a
role in irreversible withdrawal from the cell cycle in differentiating
keratinocytes. We now report that keratinocyte differentiation is also
accompanied by changes in E2F-5 subcellular localization, from the
cytoplasm to the nucleus. To define the molecular determinants of E2F-5 nuclear import, we tested its ability to enter the nucleus in import
assays in vitro using digitonin-permeabilized cells. We found that E2F-5 enters the nucleus through mediated transport processes that involve formation of nuclear pore complexes. It has been
proposed that E2F-4 and E2F-5, which lack defined nuclear localization
signal (NLS) consensus sequences, enter the nucleus in association with
NLS-containing DP-2 or pRB family proteins. However, we show
that nuclear import of E2F-5 only requires the first N-terminal 56 amino acid residues and is not dependent on interaction with DP or pRB
family proteins. Because E2F-5 is predominantly cytoplasmic in
undifferentiated keratinocytes and in other intact cells, we also
examined whether this protein is subjected to active nuclear export.
Indeed, E2F-5 is exported from the nucleus through leptomycin
B-sensitive, CRM1-mediated transport, through a region corresponding to
amino acid residues 130-154. This region excludes the DNA- and the
p130-binding domains. Thus, the subcellular distribution of E2F-5 is
tightly regulated in intact cells, through multiple functional domains
that direct nucleocytoplasmic shuttling of this protein.
Active Nuclear Import and Export Pathways Regulate E2F-5
Subcellular Localization*
,§,,¶
, and¶**
Physiology and Pharmacology
and of ¶ Paediatrics, Child Health Research Institute and
Lawson Health Research Institute, University of Western Ontario,
London, Ontario N6A 5C1, Canada
*
This work was supported with funds from the Canadian
Institutes of Health Research (CIHR) (to L. D.).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 a Kidney Foundation of Canada Scholarship.
**
Recipient of a Cancer Research Society Inc./CIHR Scholarship. To
whom correspondence should be addressed: Dept. of Physiology and
Pharmacology, Medical Sciences Bldg., University of Western Ontario,
London, Ontario N6A 5C1, Canada. Tel.: 519-661-4264; Fax: 519-661-3827;
E-mail: ldagnino@uwo.ca.
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