Regulation of the MDM2-p53 pathway by ribosomal protein L11 involves a post-ubiquitination mechanism

被引:100
作者
Dai, Mu-Shui
Shi, Dingding
Jin, Yetao
Sun, Xiao-Xin
Zhang, Yanping
Grossman, Steven R.
Lu, Hua
机构
[1] Oregon Hlth Sci Univ, Dept Biochem & Mol Biol, Sch Med, Portland, OR 97239 USA
[2] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA
[3] Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01605 USA
[4] Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC 27599 USA
关键词
D O I
10.1074/jbc.M602596200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 [生物化学与分子生物学]; 081704 [应用化学];
摘要
Inhibition of the MDM2-p53 feedback loop is critical for p53 activation in response to cellular stresses. The ribosomal proteins L5, L11, and L23 can block this loop by inhibiting MDM2-mediated p53 ubiquitination and degradation in response to ribosomal stress. Here, we show that L11, but not L5 and L23, leads to a drastic accumulation of ubiquitinated and native MDM2. This effect is dependent on the ubiquitin ligase activity of MDM2, but not p53, and requires the central MDM2 binding domain ( residues 51-108) of L11. We further show that L11 inhibited 26 S proteasome-mediated degradation of ubiquitinated MDM2 in vitro and consistently prolonged the half-life of MDM2 in cells. These results suggest that L11, unlike L5 and L23, differentially regulates the levels of ubiquitinated p53 and MDM2 and inhibits the turnover and activity of MDM2 through a post-ubiquitination mechanism.
引用
收藏
页码:24304 / 24313
页数:10
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