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J. Biol. Chem., Vol. 277, Issue 38, 35509-35515, September 20, 2002
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From the Direct experimental evidence implicates telomere
erosion as a primary cause of cellular senescence. Using a well
characterized model system for breast cancer, we define here the
molecular and cellular consequences of adriamycin treatment in breast
tumor cells. Cells acutely exposed to adriamycin exhibited an increase in p53 activity, a decline in telomerase activity, and a dramatic increase in
Adriamycin-induced Senescence in Breast Tumor Cells
Involves Functional p53 and Telomere Dysfunction*
,
,**,§**,**, and§**
Departments of Pathology, § Human
Genetics, and Pharmacology and Toxicology and the
** Massey Cancer Center, Medical College of Virginia,
Virginia Commonwealth University, Richmond, Virginia 23298-0662
-galactosidase, a marker of senescence. Inactivation of
wild-type p53 resulted in a transition of the cellular response to
adriamycin treatment from replicative senescence to delayed apoptosis,
demonstrating that p53 plays an integral role in the fate of breast
tumor cells treated with DNA-damaging agents. Stable introduction of
hTERT, the catalytic protein component of telomerase, into MCF-7 cells
caused an increase in telomerase activity and telomere length.
Treatment of MCF-7-hTERT cells with adriamycin produced an identical
senescence response as controls without signs of telomere shortening,
indicating that the senescence after treatment is telomere
length-independent. However, we found that exposure to adriamycin
resulted in an overrepresentation of cytogenetic changes involving
telomeres, showing an altered telomere state induced by adriamycin is
probably a causal factor leading to the senescence phenotype. To our
knowledge, these data are the first to demonstrate that the mechanism
of adriamycin-induced senescence is dependent on both functional p53
and telomere dysfunction rather than overall shortening.
*
This work was supported in part by the Mary Kay Ash
Charitable Foundation (to L. W. E. and S. E. H.), the Department of
Defense Breast Cancer Research Program Grant DAMD 17-01-0441 (to
D. A. G. and S. E. H.), Virginia's Commonwealth Health Research
Board (to C. K. J.-C.), and NCI, National Institutes of Health
Postdoctoral Training Grant CA 85159-01 (to P. A. M.).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.
V Foundation Scholar. To whom correspondence should be
addressed: Depts. of Pathology and Human Genetics, Medical College of
Virginia at Virginia Commonwealth University, 1101 E. Marshall St.,
Richmond, VA 23298-0662. Tel.: 804-827-0458; Fax: 804-828-5598; E-mail: seholt@hsc.vcu.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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