MDM2 Is a Negative Regulator of p21WAF1/CIP1, Independent of p53

Zhuo Zhang, Hui Wang, Mao Li, Sudhir Agrawal, Xinbin Chen, Ruiwen Zhang

Research output: Contribution to journalArticle

201 Citations (Scopus)

Abstract

The MDM2 oncogene has both p53-dependent and p53-independent activities. We have previously reported that antisense MDM2 inhibitors have significant antitumor activity in multiple human cancer models with various p53 statuses (Zhang, Z., Li, M., Wang, H., Agrawal, S., and Zhang, R. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 11636-11641). We have also provided evidence that MDM2 has a direct role in the regulation of p21, a cyclin-dependent kinase inhibitor. Here we provide evidence supporting functional interaction between MDM2 and p21 in vitro and in vivo. The inhibition of MDM2 with anti-MDM2 antisense oligonucleotide or Short Interference RNA targeting MDM2 significantly elevated p21 protein levels in PC3 cells (p53 null). In contrast, overexpression of MDM2 diminished the p21 level in the same cells by shortening the p21 half-life, an effect reversed by MDM2 antisense inhibition. MDM2 facilitates p21 degradation independent of ubiquitination and the E3 ligase function of MDM2. Instead, MDM2 promotes p21 degradation by facilitating binding of p21 with the proteasomal C8 subunit. The physical interaction between p21 and MDM2 was demonstrated both in vitro and in vivo with the binding region in amino acids 180-298 of the MDM2 protein. In summary, we provide evidence supporting a physical interaction between MDM2 and p21. We also demonstrate that, by reducing p21 protein stability via proteasome-mediated degradation, MDM2 functions as a negative regulator of p21, an effect independent of both p53 and ubiquitination.

Original languageEnglish (US)
Pages (from-to)16000-16006
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number16
DOIs
StatePublished - Apr 16 2004
Externally publishedYes

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Ubiquitination
Cyclin-Dependent Kinase Inhibitor p21
Degradation
Null Lymphocytes
Ubiquitin-Protein Ligases
Protein Stability
Antisense Oligonucleotides
Proteasome Endopeptidase Complex
RNA Interference
Oncogenes
Half-Life
Proteins
Cyclin-Dependent Kinases
Amino Acids
RNA
Neoplasms
In Vitro Techniques

ASJC Scopus subject areas

  • Biochemistry

Cite this

MDM2 Is a Negative Regulator of p21WAF1/CIP1, Independent of p53. / Zhang, Zhuo; Wang, Hui; Li, Mao; Agrawal, Sudhir; Chen, Xinbin; Zhang, Ruiwen.

In: Journal of Biological Chemistry, Vol. 279, No. 16, 16.04.2004, p. 16000-16006.

Research output: Contribution to journalArticle

Zhang, Z, Wang, H, Li, M, Agrawal, S, Chen, X & Zhang, R 2004, 'MDM2 Is a Negative Regulator of p21WAF1/CIP1, Independent of p53', Journal of Biological Chemistry, vol. 279, no. 16, pp. 16000-16006. https://doi.org/10.1074/jbc.M312264200
Zhang, Zhuo ; Wang, Hui ; Li, Mao ; Agrawal, Sudhir ; Chen, Xinbin ; Zhang, Ruiwen. / MDM2 Is a Negative Regulator of p21WAF1/CIP1, Independent of p53. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 16. pp. 16000-16006.
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