title: Mouse mammary tumor virus sequences responsible for activating cellular oncogenes.
abstract: Integration of mouse mammary tumor virus (MMTV) near the int genes results in the inappropriate expression of these proto-oncogenes and initiates events that lead to the formation of mammary adenocarcinomas. In most cases, the MMTV provirus integrates in a transcriptional orientation opposite that of the int genes. We have used a novel, vector-based system designed to recapitulate the integration of MMTV upstream of the int-2 promoter. Compared to a cellular promoter or another retroviral promoter, the MMTV long terminal repeat (LTR) in this configuration is particularly efficacious at activating the int-2 promoter. The sequences responsible for enhancing the activity of the int-2 promoter map to two domains in the 5' end of the MMTV LTR. One domain is a previously defined element; the second is an element delineated by these studies that acts synergistically with the first. Both of these elements display mammary cell-specific activity. Thus, even though the MMTV promoter itself is weak without hormonal stimulation, viral integration can position the 5' LTR elements to efficiently activate transcription from cellular proto-oncogenes. Other functional elements in the LTR have little effect on the activation of the int-2 promoter. Even stimulation of the MMTV promoter with steroid hormones only modestly activates transcription from the int-2 promoter, suggesting that the 5' elements of the LTR are the predominant determinants of the tissue- and orientation-specific activation of cellular promoters by MMTV.
authors.affiliation: Program in Molecular Biology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Grimm
authors.forename: S K
authors.initials: SK
authors.lastname: Nordeen
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000235:genetics; D004742:Enhancer Elements, Genetic; D005260:Female; D051518:Fibroblast Growth Factor 3; D005346:Fibroblast Growth Factors / Q000235:genetics; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000209:etiology / Q000235:genetics / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity*; D051379:Mice; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics; D011519:Proto-Oncogenes / Q000187:drug effects; D011533:Proviruses / Q000235:genetics; D012192:Retroviridae Infections / Q000209:etiology / Q000235:genetics / Q000821:virology; D013256:Steroids / Q000494:pharmacology; D020079:Terminal Repeat Sequences; D014162:Transfection; D014412:Tumor Virus Infections / Q000209:etiology / Q000235:genetics / Q000821:virology; D016662:Virus Integration / Q000235:genetics
chemical_list: C496444:FGF3 protein, human; C489197:Fgf3 protein, mouse; D051518:Fibroblast Growth Factor 3; D011518:Proto-Oncogene Proteins; D013256:Steroids; D005346:Fibroblast Growth Factors; D004247:DNA