MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation

Yetao Jin, Hunjoo Lee, Shelya X. Zeng, Mushui Dai, Hua Lu

Research output: Contribution to journalArticle

165 Citations (Scopus)

Abstract

The CDK inhibitor p21waf1/cip1 is degraded by a ubiquitin-independent proteolytic pathway. Here, we show that MDM2 mediates this degradation process. Overexpression of wild-type or ring finger-deleted, but not nuclear localization signal (NLS)-deleted, MDM2 decreased p21 waf1/cip1 levels without ubiquity-lating this protein and affecting its mRNA level in p53-/- cells. This decrease was reversed by the proteasome inhibitors MG132 and lactacystin, by p19arf, and by small interfering RNA (siRNA) against MDM2. p21waf1/cip1 bound to MDM2 in vitro and in cells. The p21waf1/cip1-binding-defective mutant of MDM2 was unable to degrade p21waf1/cip1. MDM2 shortened the half-life of both exogenous and endogenous p21waf1/cip1 by 50% and led to the degradation of its lysine-free mutant. Consequently, MDM2 suppressed p21waf1/cip1 induced cell growth arrest of human p53-/- and p53-/- Rb-/-cells. These results demonstrate that MDM2 directly inhibits p21waf1/cip1 function by reducing p21 waf1/cip1 stability in a ubiquitin-independent fashion.

Original languageEnglish (US)
Pages (from-to)6365-6377
Number of pages13
JournalEMBO Journal
Volume22
Issue number23
DOIs
StatePublished - Dec 1 2003

Fingerprint

Ubiquitination
Ubiquitin
Degradation
Proteasome Inhibitors
Cell growth
Small Interfering RNA
Lysine
Nuclear Localization Signals
Messenger RNA
Fingers
Half-Life
Proteins
Growth
lactacystin
benzyloxycarbonylleucyl-leucyl-leucine aldehyde

Keywords

  • MDM2
  • p21
  • Proteasome
  • Stability
  • Ubiquitin

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation. / Jin, Yetao; Lee, Hunjoo; Zeng, Shelya X.; Dai, Mushui; Lu, Hua.

In: EMBO Journal, Vol. 22, No. 23, 01.12.2003, p. 6365-6377.

Research output: Contribution to journalArticle

Jin, Yetao ; Lee, Hunjoo ; Zeng, Shelya X. ; Dai, Mushui ; Lu, Hua. / MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation. In: EMBO Journal. 2003 ; Vol. 22, No. 23. pp. 6365-6377.
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