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Molecular and Cellular Biology, February 2008, p. 1218-1229, Vol. 28, No. 4
0270-7306/08/$08.00+0     doi:10.1128/MCB.01198-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

MDMX Promotes Proteasomal Turnover of p21 at G₁ and Early S Phases Independently of, but in Cooperation with, MDM2 ^,

Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239,¹ Forschungszentrum Karlsruhe, Institute of Toxicology & Genetics, P.O. Box 3640, 76021 Karlsruhe, Germany,² Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118,³ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202⁴

Received 5 July 2007/ Returned for modification 8 October 2007/ Accepted 15 November 2007

We have shown previously that MDM2 promotes the degradation of the cyclin-dependent kinase inhibitor p21 through a ubiquitin-independent proteolytic pathway. Here we report that the MDM2 analog, MDMX, also displays a similar activity. MDMX directly bound to p21 and mediated its proteasomal degradation. Although the MDMX effect was independent of MDM2, they synergistically promoted p21 degradation when coexpressed in cells. This degradation appears to be mediated by the 26S proteasome, as MDMX and p21 bound to S2, one of the subunits of the 19S component of the 26S proteasome, in vivo. Conversely, knockdown of MDMX induced the level of endogenous p21 proteins that no longer cofractionated with 26S proteasome, resulting in G₁ arrest. The level of p21 was low at early S phase but markedly induced by knocking down either MDMX or MDM2 in human cells. Ablation of p21 rescued the G₁ arrest caused by double depletion of MDM2 and MDMX in p53-null cells. These results demonstrate that MDMX and MDM2 independently and cooperatively regulate the proteasome-mediated degradation of p21 at the G₁ and early S phases.

Published ahead of print on 17 December 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

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