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J Biol Chem, Vol. 275, Issue 12, 8991-9000, March 24, 2000
From the Department of Cellular and Molecular Medicine, Faculty of
Medicine, University of Ottawa, Ottawa,
Ontario K1H 8M5, Canada
Inactivating mutations of the von Hippel-Lindau
(VHL) tumor suppressor gene cause the VHL cancer syndrome and sporadic
renal clear cell carcinoma. VHL engages in a nucleocytoplasmic shuttle, which is required for its function. Here, we pursue our investigation to identify mechanisms by which VHL-green fluorescent protein (VHL-GFP)
is exported from the nucleus. We show that nuclear export of VHL-GFP in
living cells requires ongoing RNA polymerase II activity, and is
mediated by mechanisms that are temperature-sensitive and
energy-dependent. In vitro nuclear export of
VHL-GFP is inhibited by nuclear pore-specific lectins, requires ATP
hydrolysis and polyadenylated mRNAs, and occurs with kinetics that
are similar to those of proteins containing a nuclear export signal.
Biochemical fractionation has revealed that nuclear export of VHL-GFP
occurs by way of a Ran-dependent pathway. Size exclusion
column chromatography and deletion mutant analysis suggest that VHL-GFP
does not require assembly with one of its associated proteins,
cullin-2, to engage in nuclear export. These results demonstrate that
nuclear export of VHL-GFP is Ran-mediated and ATP
hydrolysis-dependent. They also suggest that sequences
outside the elongin C binding box may function as a nuclear export
domain, potentially providing a novel role for this region of VHL
frequently mutated in renal cell carcinoma.
Ran-mediated Nuclear Export of the von Hippel-Lindau Tumor
Suppressor Protein Occurs Independently of Its Assembly with
Cullin-2*
*
This work was supported in part by an operating grant from
the Medical Research Council of Canada (to S. 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.
Scholar of the Medical Research Council. To whom correspondence
should be addressed: Dept. of Cellular and Molecular Medicine, Faculty
of Medicine, University of Ottawa, 451 Smyth Rd., Ottawa, Ontario K1H
8M5, Canada. Tel.: 613-562-5800 (ext. 8385); Fax: 613-562-5636; E-mail:
slee@uottawa.ca.
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