title: Regulation of the HDM2-p53 pathway by ribosomal protein L6 in response to ribosomal stress.
abstract: The HDM2-p53 loop is crucial for monitoring p53 level and human pathologies. Therefore, identification of novel molecules involved in this regulatory loop is necessary for understanding the dynamic regulation of p53 and treatment of human diseases. Here, we characterized that the ribosomal protein L6 binds to and suppresses the E3 ubiquitin ligase activity of HDM2, and subsequently attenuates HDM2-mediated p53 polyubiquitination and degradation. The enhanced p53 activity further slows down cell cycle progression and leads to cell growth inhibition. Conversely, the level of p53 is dramatically decreased upon the depletion of RPL6, indicating that RPL6 is essential for p53 stabilization. We also found that RPL6 translocalizes from the nucleolus to nucleoplasm under ribosomal stress, which facilitates its binding with HDM2. The interaction of RPL6 and HDM2 drives HDM2-mediated RPL6 polyubiquitination and proteasomal degradation. Longer treatment of actinomycin D increases RPL6 ubiquitination and destabilizes RPL6, and thereby putatively attenuates p53 response until the level of L6 subsides. Therefore, RPL6 and HDM2 form an autoregulatory feedback loop to monitor the level of p53 in response to ribosomal stress. Together, our study identifies the crucial function of RPL6 in regulating HDM2-p53 pathway, which highlights the importance of RPL6 in human genetic diseases and cancers.
authors.affiliation: State Key Lab of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China and Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Bai
authors.forename: Jinfang
authors.initials: J
authors.lastname: Zhang
authors.forename: Weichun
authors.initials: W
authors.lastname: Xiao
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zheng
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D006801:Humans; D051379:Mice; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000378:metabolism*; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C031249:ribosomal protein L6; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2