Regulation of the MDM2-p53 pathway by ribosomal protein L11 involves a post-ubiquitination mechanism.
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.
Dai
Mu-Shui
MS
Department of Biochemistry and Molecular Biology, School of Medicine, Oregon Health and Science University, Portland, Oregon 97239.
Shi
Dingding
D
Jin
Yetao
Y
Sun
Xiao-Xin
XX
Zhang
Yanping
Y
Grossman
Steven R
SR
Lu
Hua
H
D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C027624:ribosomal protein L11; C032493:ribosomal protein L17; C029742:ribosomal protein L5; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex