Novel Mechanisms of Mammary Oncogenesis by Human Adenovirus Type 9
Abstract
The purpose of this proposal was to elucidate novel mechanisms of breast cancer development. Toward this goal, transformation by the E4-ORF1 oncoprotein of Ad9, a virus that generates exclusively estrogen-dependent mammary tumors in rats, was linked to its ability to bind and sequester the cellular PDZ-proteins MUPP1, MAUI-i, DLG, and ZO-2 in cells. Moreover, over-expression of ZO-2, a candidate tumor suppressor protein associated with breast cancer, inhibited Ad9 E4-ORF1-induced transformation. Transformation by Ad9 E4-ORF1 was likewise linked to its ability to activate cellular phosphoinositide 3-kinase (PI 3-K), and this activity depended on interactions of Ad9 E4-ORF1 with its cellular PDZ-protein targets. Additionally, we showed that MAUI-i forms a complex with the tumor suppressor protein PTEN, a lipid phosphatase that antagonizes PI 3-K, and that MAUI-i and PTEN synergize to block Ad9 E4-ORF1-induced PI 3-K stimulation. Coupled with the fact that Ad9 E4-ORF1 could activate PI 3-K signaling in PTEN-null cells, our findings suggest that Ad9 E4-ORF1-induced PI 3-K pathway activation involves both PTEN-dependent and -independent mechanisms.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2001
- Accession Number
- ADA396621
Entities
People
- Ronald Javier
Organizations
- Baylor College of Medicine