Susceptibility of p53 Unstructured N Terminus to 20 S Proteasomal Degradation Programs the Stress Response*♦
- From the ‡Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel and
- the §Department of Biological Sciences, Columbia University, New York, New York 10027
- ↵1 The Oscar and Emma Getz Professor. To whom correspondence should be addressed. Tel.: 972-8-934-2320; Fax: 972-8-934-4108; E-mail: yosef.shaul{at}weizmann.ac.il.
Abstract
The N-terminal transcription activation domain of p53 is intrinsically unstructured. We show in vitro and in vivo that this domain initiates p53 degradation by the 20 S proteasome in a ubiquitin-independent fashion. The decay of metabolically labeled p53 follows biphasic kinetics with an immediate fast phase that is ubiquitin-independent and a second slower phase that is ubiquitin-dependent. The 20 S proteasome executes the first phase by default, whereas the second phase requires the 26 S proteasome. p53 N-terminal binding proteins, such as Hdmx, can selectively block the first phase of degradation. Remarkably, γ-irradiation inhibits both p53 decay phases, whereas UV selectively negates the second phase, giving rise to discrete levels of p53 accumulation. Our data of a single protein experiencing double mode degradation mechanisms each with unique kinetics provide the mechanistic basis for programmable protein homeostasis (proteostasis).
Footnotes
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↵* This work was supported by grants from the Samuel Waxman Cancer Research Foundation, from the Israel Science Foundation, and from the Minerva Foundation with funding from the Federal German Ministry for Education and Research and Journal of Cell Science student travel fellowship.
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↵♦ This article was selected as a Paper of the Week.
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The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3 and a table.
- Received July 2, 2009.
- Revision received July 16, 2009.
- © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
