MDM2 gene amplification and transcript levels in human sarcomas: relationship to TP53 gene status.
Background: Alterations of the TP53 tumor suppressor gene appear to be implicated in the tumorigenesis and progression of several types of human cancer, including different histologic subtypes of sarcomas. The MDM2 (murine double minute-2) gene encodes a nuclear phosphoprotein that may interact with...
| Publicado en: | JNCI: Journal of the National Cancer Institute Vol. 86; no. 17; pp. 1297 - 1303 |
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| Autores principales: | , , , , , |
| Formato: | research Journal Article |
| Publicado: |
Oxford University Press / USA
9/7/94
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=119722580&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 119722580 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00278874 JNC jtl: JNCI: Journal of the National Cancer Institute issn: 00278874 maglogo: N pubinfo: dt: 9/7/94 vid: 86 iid: 17 pid: 622 pub: Oxford University Press / USA artinfo: ui: 119722580 NLM8064888 119722580 10.1093/jnci/86.17.1297 NLM8064888 119722580 ppf: 1297 ppct: 6 formats: tig: atl: MDM2 gene amplification and transcript levels in human sarcomas: relationship to TP53 gene status. aug: au: Flørenes, V A Maelandsmo, G M Forus, A Andreassen, A Myklebost, O Fodstad, O affil: Department of Tumor Biology, Norwegian Radium Hospital, Oslo sug: subj: Proteins Nuclear Proteins Oncogenes Sarcoma Blotting, Northern Blotting, Southern Gene Amplification Mice DNA Probes Sequence Analysis RNA Analysis Human Animal Studies Validation Studies Comparative Studies Evaluation Research Multicenter Studies Clinical Assessment Tools ab: Background: Alterations of the TP53 tumor suppressor gene appear to be implicated in the tumorigenesis and progression of several types of human cancer, including different histologic subtypes of sarcomas. The MDM2 (murine double minute-2) gene encodes a nuclear phosphoprotein that may interact with both mutant and wild-type p53 proteins, thereby inhibiting p53-mediated transactivation in a dose-dependent manner. Recently it has been suggested that mdm2 and p53 proteins are components of an autoregulatory loop in which the MDM2 gene is transactivated by p53.Purpose: Our purpose was to examine the frequency of MDM2 amplifications in larger panels of sarcomas, determine if the mRNA level could be elevated in tumors without concomitant gene amplification, and relate MDM2 findings to the TP53 status of the tumors.Methods: Sarcoma tissue of different histologic subtypes was obtained from 68 patients at the time of surgery and from 26 human xenografts in nude mice. In addition, two human sarcoma cell lines (OSA and U2OS) were studied. Genomic DNA from tumor tissue, in vitro cell lines, and peripheral blood cells were isolated by Southern-blot analysis methods to determine MDM2 gene amplification. Tumor DNA was analyzed for possible TP53 gene mutations in exons 5, 7, and 8 by constant denaturing gel electrophoresis. To determine the MDM2 and TP53 mRNA levels, Northern-blot analysis was performed.Results: Amplification of the MDM2 gene was detected in 10 tumors (10.3%). Whereas MDM2 amplification and/or over-expression were found only in two (U2OS and OSA cell lines) of 18 osteosarcomas, one of 20 malignant fibrous histiocytomas (MFHs), and in none of 14 leiomyosarcomas, such alterations were observed in two of two fibrosarcomas, three of six malignant schwannomas, three of 19 liposarcomas, and in the one hemangiopericytoma examined. MDM2 overexpression was found in all nine examined cases with and in three tumors without amplification. TP53 mutations were detected in 12 cases (five osteosarcomas, four MFHs, and three leiomyosarcomas), of which none showed amplification, but one had increased levels of MDM2 mRNA. None of the fibrosarcomas, malignant schwannomas, and liposarcomas examined had mutated TP53. The six sarcomas that showed high TP53 mRNA expression in the absence of gene mutation also had elevated levels of MDM2 mRNA.Conclusions: The present data provide further indications that increased MDM2 expression level, caused by gene amplification or altered regulation of transcription, is involved in tumor progression of some, but not all, sarcoma subtypes. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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