Tsvetkov, Peter; Reuven, Nina; Prives, Carol; Shaul, Yosef

Journal of Biological Chemistry (2009), 284(39), 26234-26242 CODEN: JBCHA3; ISSN: 0021-9258. English.

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, .gamma.-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).