Proviral insertions within the int-2 gene can generate multiple anomalous transcripts but leave the protein-coding...

Area of Science:

• Oncology
• Virology
• Molecular Biology

Background:

• Mouse mammary tumor virus (MMTV) is implicated in inducing breast tumors.
• The int-2 proto-oncogene plays a role in mammary development and tumorigenesis.

Purpose of the Study:

• To investigate how MMTV proviral integration affects int-2 proto-oncogene transcription and RNA products in virally induced breast tumors.
• To determine if proviral insertions disrupt the int-2 gene's coding sequence.

Main Methods:

• Analysis of RNA transcripts from int-2 in 20 MMTV-induced breast tumors.
• RNase protection experiments to identify transcript initiation and termination sites.
• Detailed examination of proviral insertion sites relative to int-2 promoters and exons.

Main Results:

• Proviral insertion, upstream or downstream of int-2, activated transcription from three different promoters.
• Insertions within the transcription unit disrupted RNA structures, with some transcripts initiating from the viral long terminal repeat or cryptic int-2 promoters.
• Proviral insertions in the 3' untranslated region provided alternative polyadenylation signals.
• Crucially, no proviral insertion perturbed the int-2 gene's open reading frame.

Conclusions:

• MMTV integration significantly alters int-2 gene expression through complex transcriptional activation and RNA processing modifications.
• The int-2 gene product, related to fibroblast growth factor, is implicated as a contributing factor in MMTV-induced mammary tumors, despite the coding sequence remaining intact.