TY - JOUR
T1 - Regulation of the MDM2-p53 pathway by ribosomal protein L11 involves a post-ubiquitination mechanism
AU - Dai, Mu Shui
AU - Shi, Dingding
AU - Jin, Yetao
AU - Sun, Xiao Xin
AU - Zhang, Yanping
AU - Grossman, Steven R.
AU - Lu, Hua
PY - 2006/8/25
Y1 - 2006/8/25
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M602596200
DO - 10.1074/jbc.M602596200
M3 - Article
C2 - 16803902
AN - SCOPUS:33747654496
SN - 0021-9258
VL - 281
SP - 24304
EP - 24313
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 34
ER -