 | CELL SIGNALING, TRANSCRIPTION, AND TRANSLATION AS THERAPEUTIC TARGETS
Copyright © 2002 by the New York Academy of Sciences
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Annals of the New York Academy of Sciences 973:374-383 (2002)
© 2002 New York Academy of Sciences
Regulation of p53
Intricate Loops and Delicate Balances
MOSHE ORENa,
ALEXANDER DAMALASa,
TANYA GOTTLIEBa,
DAN MICHAELa,
JAN TAPLICKa,
JUAN FERNANDO MARTINEZ LEALa,
RUTH MAYAa,
MIRI MOASa,
RONY SEGERb,
YOICHI TAYAc AND
AVRI BEN-ZE'EVa
aDepartments of Molecular Cell Biology and bBiological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel
cRadiobiology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan
Address for correspondence: Dr. Moshe Oren, Department of Molecular Cell Biology, The Weizmann Institute of Science, POB 26, Rehovot 76100, Israel. Voice: 972-8-9342358; fax: 972-8-9346004.
moshe.oren{at}weizmann.ac.il
Ann. N.Y. Acad. Sci. 973: 374-383 (2002).
The p53 tumor suppressor protein provides a major anti-cancer defense mechanism, as underscored by the fact that the p53 gene is the most frequent target for genetic alterations in human cancer. Recent work has led to the realization that p53 lies at the hub of a very complex network of signaling pathways that integrate a variety of intracellular and extracellular inputs. Part of this network consists of an array of autoregulatory feedback loops, where p53 exhibits very intricate interactions with other proteins known to play important roles in the determination of cell fate. We discuss two such loops, one involving the ß-catenin protein and the other centering on the Akt/PKB protein kinase. In both cases, the central module is the interplay between p53 and the Mdm2 protein, which inactivates p53 and targets it for rapid proteolysis. Whereas deregulated ß-catenin can lead to Mdm2 inactivation and p53 accumulation, active p53 can promote the degradation and down-regulation of ß-catenin. Similarly, Akt can block p53 activation by potentiating Mdm2, whereas activated p53 can tune down Akt in several different ways. In each case, the actual output of the loop is determined by the delicate balance between the opposing effects of its different components. Often, this balance is dictated by additional signaling processes that occur simultaneously within the same cell. Genetic alterations characteristic of cancer are capable of severely distorting this balance, thereby overriding the tumor suppressor effects of p53 in a manner that facilitates neoplastic conversion.
Key Words: p53 • murine double-minute 2 • apoptosis • ß-catenin • ARF • Akt • ubiquitination
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