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J. Biol. Chem., Vol. 276, Issue 23, 20566-20571, June 8, 2001
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From the Each nuclear pore is responsible for both nuclear
import and export with a finite capacity for bidirectional transport
across the nuclear envelope. It remains poorly understood how the
nuclear transport pathway responds to increased demands for
nucleocytoplasmic communication. A case in point is cellular
hypertrophy in which increased amounts of genetic material need to be
transported from the nucleus to the cytosol. Here, we report an
adaptive down-regulation of nuclear import supporting such an increased
demand for nuclear export. The induction of cardiac cell hypertrophy by
phenylephrine or angiotensin II inhibited the nuclear translocation of
H1 histones. The removal of hypertrophic stimuli reversed the
hypertrophic phenotype and restored nuclear import. Moreover, the
inhibition of nuclear export by leptomycin B rescued import.
Hypertrophic reprogramming increased the intracellular GTP/GDP ratio
and promoted the nuclear redistribution of the GTP-binding transport
factor Ran, favoring export over import. Further, in hypertrophy, the reduced creatine kinase and adenylate kinase activities limited energy
delivery to the nuclear pore. The reduction of activities was
associated with the closure of the cytoplasmic phase of the nuclear
pore preventing import at the translocation step. Thus, to overcome the
limited capacity for nucleocytoplasmic transport, cells requiring
increased nuclear export regulate the nuclear transport pathway
by undergoing a metabolic and structural restriction of nuclear import.
Directed Inhibition of Nuclear Import in Cellular
Hypertrophy*
§¶,§,
,**,§
Division of Cardiovascular Diseases,
Department of Medicine, the § Department of Molecular
Pharmacology and Experimental Therapeutics, and the ¶ Department
of Physical Medicine and Rehabilitation, Mayo Clinic, Mayo Foundation,
Rochester, Minnesota 55905
*
This work was supported by the American Heart Association,
the Clinician-Investigator Program at the Mayo Clinic, the Miami Heart
Research Institute, the Bruce and Ruth Rappaport Program in Vascular
Biology and Gene Delivery, and the Marriott Foundation and by Grants
HL64822 and HL07111 from the National Institutes of Health.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.
Present address: CNRS CRBM UPR1086, Montpellier, France.
**
Present address: Department of Geriatrics, University of
Geneva, Geneva, Switzerland.
An Established Investigator of the American Heart Association.
To whom correspondence should be addressed: Guggenheim 7, Mayo Clinic,
Rochester, MN 55905. Tel.: 507-284-2747; Fax: 507-284-9111; E-mail:
terzic.andre@mayo.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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