Identification of a sequence element from p53 that signals for Mdm2-targeted degradation.

Abstract:

:The binding of Mdm2 to p53 is required for targeting p53 for degradation. p73, however, binds to Mdm2 but is refractory to Mdm2-mediated degradation, indicating that binding to Mdm2 is not sufficient for degradation. By utilizing the structural homology between p53 and p73, we generated p53-p73 chimeras to determine the sequence element unique to p53 essential for regulation of its stability. We found that replacing an element consisting of amino acids 92 to 112 of p53 with the corresponding region of p73 results in a protein that is not degradable by Mdm2. Removal of amino acids 92 to 112 of p53 by deletion also results in a non-Mdm2-degradable protein. Significantly, the finding that swapping this fragment converts p73 from refractory to sensitive to Mdm2-mediated degradation supports the conclusion that the amino acids 92 to 112 of p53 function as a degradation signal. We propose that the presence of an additional protein recognizes the degradation signal and coordinates with Mdm2 to target p53 for degradation. Our finding opens the possibility of searching for the additional protein, which most likely plays a critical role in the regulation of p53 stability and therefore function.

journal_name

Mol Cell Biol

authors

Gu J,Chen D,Rosenblum J,Rubin RM,Yuan ZM

doi

10.1128/mcb.20.4.1243-1253.2000

subject

Has Abstract

pub_date

2000-02-01 00:00:00

pages

1243-53

issue

4

eissn

0270-7306

issn

1098-5549

journal_volume

20

pub_type

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