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Molecular and Cellular Biology, August 2003, p. 5113-5121, Vol. 23, No. 15
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.15.5113-5121.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

MDM2 Promotes Ubiquitination and Degradation of MDMX

Yu Pan and Jiandong Chen*

Molecular Oncology Program, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, Tampa, Florida 33612

Received 21 November 2002/ Returned for modification 6 January 2003/ Accepted 7 May 2003

The p53 tumor suppressor is regulated by MDM2-mediated ubiquitination and degradation. Mitogenic signals activate p53 by induction of ARF expression, which inhibits p53 ubiquitination by MDM2. Recent studies showed that the MDM2 homolog MDMX is also an important regulator of p53. We present evidence that MDM2 promotes MDMX ubiquitination and degradation by the proteasomes. This effect is stimulated by ARF and correlates with the ability of ARF to bind MDM2. Promotion of MDM2-mediated MDMX ubiquitination requires the N-terminal domain of ARF, which normally inhibits MDM2 ubiquitination of p53. An intact RING domain of MDM2 is also required, both to interact with MDMX and to provide E3 ligase function. Increase of MDM2 and ARF levels by DNA damage, recombinant ARF adenovirus infection, or inducible MDM2 expression leads to proteasome-mediated down-regulation of MDMX levels. Therefore, MDMX and MDM2 are coordinately regulated by stress signals. The ARF tumor suppressor differentially regulates the ability of MDM2 to promote p53 and MDMX ubiquitination and activates p53 by targeting both members of the MDM2 family.

* Corresponding author. Mailing address: H. Lee Moffitt Cancer Center, MRC3057A, 12902 Magnolia Dr., Tampa, FL 33612. Phone: (813) 903-6822. Fax: (813) 903-6817. E-mail: jchen{at}moffitt.usf.edu.

Molecular and Cellular Biology, August 2003, p. 5113-5121, Vol. 23, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.15.5113-5121.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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