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Molecular and Cellular Biology, February 2000, p. 1243-1253, Vol. 20, No. 4
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Identification of a Sequence Element from p53 That Signals for Mdm2-Targeted Degradation

Jijie Gu, Dongli Chen, Jamie Rosenblum, Rachel M. Rubin, and Zhi-Min Yuan*

Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts 02115

Received 4 August 1999/Returned for modification 24 September 1999/Accepted 21 November 1999

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.

* Corresponding author. Mailing address: Department of Cancer Cell Biology (Bldg. 1, Room 209), Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115. Phone: (617) 432-0763. Fax: (617) 432-0107. E-mail: zyuan{at}hsph.harvard.edu.

Molecular and Cellular Biology, February 2000, p. 1243-1253, Vol. 20, No. 4
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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