title: RPL23 Links Oncogenic RAS Signaling to p53-Mediated Tumor Suppression.
abstract: The ribosomal protein (RP)-MDM2 interaction is a p53 response pathway critical for preventing oncogenic c-MYC-induced tumorigenesis. To investigate whether the RP-MDM2-p53 pathway is a broad antioncogenic mechanism, we crossed mice bearing an MDM2(C305F) mutation, which disrupts RPL11 binding to MDM2, with mice expressing an oncogenic Hras(G12V) transgene. Interestingly, the MDM2(C305F)-mutant mice, which are hypersensitive to c-MYC-induced tumorigenesis, are not hypersensitive to oncogenic Hras(G12V)-induced tumorigenesis. Unlike c-MYC, which induces expression of RPL11, RAS overexpression leads to an increase in RPL23 mRNA and protein whereas RPL11 expression remains unchanged. The induction of RPL23 involves both MEK and PI3K signaling pathways and requires mTOR function. Increased expression of RPL23, which maintains binding to MDM2(C305F) mutant, correlates with increased p53 expression in MDM2(C305F) cells. Furthermore, RAS overexpression can induce p53 in the absence of p19ARF, and the induction can be abolished by downregulation of RPL23. Thus, although the RPL11-MDM2-p53 pathway coordinates with the p19ARF-MDM2-p53 pathway against oncogenic c-MYC-induced tumorigenesis, the RPL23-MDM2-p53 pathway coordinates with the p19ARF-MDM2-p53 pathway against oncogenic RAS-induced tumorigenesis. Cancer Res; 76(17); 5030-9. ©2016 AACR.
authors.affiliation: Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China. Hospital and Institute of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing, China. School of Basic Medical Sciences and Institute of System Biomedicine, Peking University, Beijing, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Tackmann
authors.affiliation: Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Shijie
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Hospital and Institute of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing, China. School of Basic Medical Sciences and Institute of System Biomedicine, Peking University, Beijing, China. Beijing Tsinghua Changgung Hospital, Tsinghua Medical Center, Changping District, Beijing, China.
authors.forename: Jiahong
authors.initials: J
authors.lastname: Dong
authors.affiliation: School of Basic Medical Sciences and Institute of System Biomedicine, Peking University, Beijing, China.
authors.forename: Congying
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Adrienne D
authors.initials: AD
authors.lastname: Cox
authors.affiliation: Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China. Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. ypzhang@med.unc.edu.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D012269:Ribosomal Proteins; C486193:Rpl23 protein, mouse; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D016283:Proto-Oncogene Proteins p21(ras)