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Mouse mammary tumor virus sequences responsible for activating cellular oncogenes

S L Grimm1, S K Nordeen

  • 1Program in Molecular Biology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.

Journal of Virology
|November 13, 1998
PubMed

Insights

Mouse mammary tumor virus (MMTV) integration near int genes activates proto-oncogenes, leading to mammary tumors. Specific MMTV LTR elements strongly activate the int-2 promoter in mammary cells, driving tumor formation.

Area of Science:

  • * Molecular biology
  • * Cancer research
  • * Virology

Background:

  • * Mouse mammary tumor virus (MMTV) integration near proto-oncogenes like int-2 can lead to mammary adenocarcinomas.
  • * MMTV provirus integration is often in a transcriptional orientation opposite to the target proto-oncogenes.

Purpose of the Study:

  • * To investigate the mechanism by which MMTV integration activates cellular proto-oncogenes.
  • * To identify specific elements within the MMTV long terminal repeat (LTR) responsible for activating the int-2 promoter.

Main Methods:

  • * Development of a novel vector-based system to mimic MMTV integration upstream of the int-2 promoter.
  • * Comparative analysis of promoter activation by MMTV LTR versus cellular or other retroviral promoters.
  • * Mapping of MMTV LTR sequences responsible for enhancing int-2 promoter activity.

Main Results:

  • * The MMTV LTR, when integrated upstream of int-2, is highly effective at activating the int-2 promoter, surpassing other promoters.
  • * Two distinct domains within the 5' end of the MMTV LTR were identified as crucial for enhancing int-2 promoter activity.
  • * These activating elements exhibit mammary cell-specific activity and act synergistically.
  • * Hormonal stimulation of the MMTV promoter only modestly increased int-2 transcription, indicating the primary role of LTR elements.

Conclusions:

  • * Viral integration can position MMTV LTR elements to efficiently activate transcription of cellular proto-oncogenes.
  • * The 5' elements of the MMTV LTR are the primary drivers of tissue- and orientation-specific activation of cellular promoters.
  • * These findings elucidate a key mechanism in MMTV-induced mammary tumorigenesis.

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