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: S L Grimm, S K Nordeen
• Journal: Journal of virology (J Virol) Vol. 72 Issue 12 Pg. 9428-35 (Dec 1998) ISSN: 0022-538X [Print] United States
• PMID: 9811675 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• FGF3 protein, human
• Fgf3 protein, mouse
• Fibroblast Growth Factor 3
• Proto-Oncogene Proteins
• Steroids
• Fibroblast Growth Factors
• DNA

Topics

• Animals
• Base Sequence
• Cell Line
• DNA (genetics)
• Enhancer Elements, Genetic
• Female
• Fibroblast Growth Factor 3
• Fibroblast Growth Factors (genetics)
• Gene Expression Regulation
• Genetic Vectors
• HeLa Cells
• Humans
• Mammary Neoplasms, Experimental (etiology, genetics, virology)
• Mammary Tumor Virus, Mouse (drug effects, genetics, pathogenicity)
• Mice
• Promoter Regions, Genetic (drug effects)
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogenes (drug effects)
• Proviruses (genetics)
• Retroviridae Infections (etiology, genetics, virology)
• Steroids (pharmacology)
• Terminal Repeat Sequences
• Transfection
• Tumor Virus Infections (etiology, genetics, virology)
• Virus Integration (genetics)