Regulation of the MDM2-p53 pathway by the nucleolar protein CSIG in response to nucleolar stress.
Nucleolar proteins play an important role in the regulation of the MDM2-p53 pathway, which coordinates cellular response to stress. However, the mechanism underlying this regulation remains poorly understood. Here, we report that the nucleolar protein CSIG is a novel and crucial regulator of the MDM2-p53 pathway. We demonstrate that CSIG translocates from the nucleolus to the nucleoplasm in response to nucleolar stress. Moreover, knockdown of CSIG attenuates the induction of p53 and abrogates G1 phase arrest in response to nucleolar stress. CSIG interacts directly with the MDM2 RING finger domain and inhibits MDM2 E3 ubiquitin ligase activity, thus resulting in a decrease in MDM2-mediated p53 ubiquitination and degradation. Our results suggest that the CSIG-MDM2-p53 regulatory pathway plays an important role in the cellular response to nucleolar stress.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Peking University Research Center on Aging, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, 38 Xueyuan Road, Beijing 100191, PR China.
Nan
N
Xie
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Peking University Research Center on Aging, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, 38 Xueyuan Road, Beijing 100191, PR China.
Liwei
L
Ma
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Peking University Research Center on Aging, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, 38 Xueyuan Road, Beijing 100191, PR China.
Feng
F
Zhu
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Peking University Research Center on Aging, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, 38 Xueyuan Road, Beijing 100191, PR China.
Wenhui
W
Zhao
Department of Laboratory Animal Science, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, PR China.
Feng
F
Tian
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Peking University Research Center on Aging, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, 38 Xueyuan Road, Beijing 100191, PR China.
Fuwen
F
Yuan
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Peking University Research Center on Aging, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, 38 Xueyuan Road, Beijing 100191, PR China.
Jingxuan
J
Fu
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Peking University Research Center on Aging, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, 38 Xueyuan Road, Beijing 100191, PR China.
Daoyuan
D
Huang
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Peking University Research Center on Aging, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, 38 Xueyuan Road, Beijing 100191, PR China.
Cuicui
C
Lv
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Peking University Research Center on Aging, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, 38 Xueyuan Road, Beijing 100191, PR China.
Tanjun
T
Tong
D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D002466:Cell Nucleolus / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D011257:Pregnancy Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012335:RNA, Ribosomal / Q000378:metabolism; D012269:Ribosomal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
D011257:Pregnancy Proteins; D012335:RNA, Ribosomal; C117409:RSL1D1 protein, human; D012269:Ribosomal Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex