title: Intracellular CD24 disrupts the ARF-NPM interaction and enables mutational and viral oncogene-mediated p53 inactivation.
abstract: CD24 is overexpressed in nearly 70% human cancers, whereas TP53 is the most frequently mutated tumour-suppressor gene that functions in a context-dependent manner. Here we show that both targeted mutation and short hairpin RNA (shRNA) silencing of CD24 retard the growth, progression and metastasis of prostate cancer. CD24 competitively inhibits ARF binding to NPM, resulting in decreased ARF, increase MDM2 and decrease levels of p53 and the p53 target p21/CDKN1A. CD24 silencing prevents functional inactivation of p53 by both somatic mutation and viral oncogenes, including the SV40 large T antigen and human papilloma virus 16 E6-antigen. In support of the functional interaction between CD24 and p53, in silico analyses reveal that TP53 mutates at a higher rate among glioma and prostate cancer samples with higher CD24 mRNA levels. These data provide a general mechanism for functional inactivation of ARF and reveal an important cellular context for genetic and viral inactivation of TP53.
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Lizhong
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Runhua
authors.initials: R
authors.lastname: Liu
authors.affiliation: Center for Cancer and Immunology Research and Division of Pathology, Children's Research Institute, Children's National Medical Center, Washington DC 20010, USA.
authors.forename: Peiying
authors.initials: P
authors.lastname: Ye
authors.affiliation: 1] Center for Cancer and Immunology Research and Division of Pathology, Children's Research Institute, Children's National Medical Center, Washington DC 20010, USA [2] Program of Immunology, Integrated Biomedical Graduate Program, University of Michigan School of Medicine, Ann Arbor, Michigan 48103, USA.
authors.forename: Chunshu
authors.initials: C
authors.lastname: Wong
authors.affiliation: Center for Cancer and Immunology Research and Division of Pathology, Children's Research Institute, Children's National Medical Center, Washington DC 20010, USA.
authors.forename: Guo-Yun
authors.initials: GY
authors.lastname: Chen
authors.affiliation: Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Penghui
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Center for Cancer and Immunology Research and Division of Pathology, Children's Research Institute, Children's National Medical Center, Washington DC 20010, USA.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Sakabe
authors.affiliation: OncoImmune, Inc., Rockville, Maryland 20852, USA.
authors.forename: Xincheng
authors.initials: X
authors.lastname: Zheng
authors.affiliation: OncoImmune, Inc., Rockville, Maryland 20852, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
authors.forename: Taijiao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Radiation Oncology, School of Medicine, University of Michigan, Ann Arbor, Michigan 48105, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Bassetti
authors.affiliation: Center for Cancer and Immunology Research and Division of Pathology, Children's Research Institute, Children's National Medical Center, Washington DC 20010, USA.
authors.forename: Sandro
authors.initials: S
authors.lastname: Jube
authors.affiliation: Department of Radiation Oncology, School of Medicine, University of Michigan, Ann Arbor, Michigan 48105, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Cancer and Immunology Research and Division of Pathology, Children's Research Institute, Children's National Medical Center, Washington DC 20010, USA.
authors.forename: Pan
authors.initials: P
authors.lastname: Zheng
authors.affiliation: Center for Cancer and Immunology Research and Division of Pathology, Children's Research Institute, Children's National Medical Center, Washington DC 20010, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051927:CD24 Antigen; D050759:Cyclin-Dependent Kinase Inhibitor p21; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2