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Cell. 2002 May 3;109(3):335-46.

A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy.

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1
Cold Spring Harbor Laboratory, 1 Bungtown Road, New York 11724, USA.

Abstract

p53 and INK4a/ARF mutations promote tumorigenesis and drug resistance, in part, by disabling apoptosis. We show that primary murine lymphomas also respond to chemotherapy by engaging a senescence program controlled by p53 and p16(INK4a). Hence, tumors with p53 or INK4a/ARF mutations-but not those lacking ARF alone-respond poorly to cyclophosphamide therapy in vivo. Moreover, tumors harboring a Bcl2-mediated apoptotic block undergo a drug-induced cytostasis involving the accumulation of p53, p16(INK4a), and senescence markers, and typically acquire p53 or INK4a mutations upon progression to a terminal stage. Finally, mice bearing tumors capable of drug-induced senescence have a much better prognosis following chemotherapy than those harboring tumors with senescence defects. Therefore, cellular senescence contributes to treatment outcome in vivo.

PMID:
12015983
DOI:
10.1016/s0092-8674(02)00734-1
[Indexed for MEDLINE]
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