title: Genome-scale functional analysis of the human genes modulating p53 activity by regulating MDM2 expression in a p53-independent manner.
abstract: MDM2, a critical negative regulator of p53, is often overexpressed in leukemia, but few p53 mutations are found, suggesting that p53-independent MDM2 expression occurs due to alterations in MDM2 upstream regulators. In this study, a high MDM2 transcription level was observed (41.17%) regardless of p53 expression in patient with acute myeloid leukemia (AML). Therefore, we performed genome-scale functional screening of the human genes modulating MDM2 expression in a p53-independent manner. We searched co-expression profiles of genes showing a positive or negative pattern with MDM2 expression in a DNA microarray database, selected1089 links, and composed a screening library of 368 genes. Using MDM2 P1 and P2 promoter-reporter systems, we screened clones regulating MDM2 transcriptions in a p53-independent manner by overexpression. Nine clones from the screening library showed enhanced MDM2 promoter activity and MDM2 expression in p53-deficient HCT116 cells. Among them, six clones, including NTRK2, GNA15, SFRS2, EIF5A, ELAVL1, and YWHAB mediated MAPK signaling for expressing MDM2. These results indicate that p53-independent upregulation of MDM2 by increasing selected clones may lead to oncogenesis in AML and that MDM2-modulating genes are novel potential targets for AML treatment.
authors.affiliation: Center for Applied Life Science, Hanbat National University, Taejon, 305-719, Republic of Korea.
authors.forename: Dong Min
authors.initials: DM
authors.lastname: Kim
authors.affiliation: Genome Research Center for Hematopoietic Diseases, Chonnam National University Hwasun Hospital, Hwasun, 519-763, Republic of Korea.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahangno, Yuseong-gu, Daejeon, 305-806, Republic of Korea.
authors.forename: Young Il
authors.initials: YI
authors.lastname: Yeom
authors.affiliation: New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea. Electronic address: shmin03@gmail.com.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Min
authors.affiliation: Department of Biology, Chonnam National University, Gwangju, 500-757, Republic of Korea. Electronic address: ickim@chonnam.ac.kr.
authors.forename: Il-Chul
authors.initials: IC
authors.lastname: Kim
mesh_terms: D001483:Base Sequence; D002470:Cell Survival / Q000235:genetics; D030541:Databases, Genetic; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D045325:HCT116 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D020928:Mitogen-Activated Protein Kinases
keywords: High-throughput screening; Leukemia; MDM2; MDM2-modulating gene; p53