Selective Chemosensitization of Rb Mutant Cells
Abstract
The primary objective of this project ultimately is to develop strategies that specifically kill breast cancer cells. The adenoviral oncoprotein E1A serves as a tool to understand how both normal and tumor cells become chemosensitive. E1A confers chemosensitivity and p53 potentates E1A function. Signaling to p53 involves the p19(ARF) tumor suppressor gene. Furthermore, at least two functions within the N-terminal region of E1A are required to confer chemosensitivity and stabilize p53 in normal cells. One of these functions is to inactivate the retinoblastoma gene product. E1A mutants unable to inactivate Rb but retaining the N-terminal function selectively promote chemosensitivity in cells lacking an intact Rb pathway. Elucidating the other function(s) of E1A involved in mediating chemosensitivity remains a major goal. Contrary to what was previously thought, a refined mutational analysis of the N-terminal region of E1A provides strong evidence that the ability of E1A to interact with either p300 or CBP does not correlate with E1A-mediated chemosensitivity or p53 stabilization. Finally, an N-terminal fragment of E1A unable to bind p300/CBP and missing C-terminal functions is sufficient to confer chemosensitivity. Ongoing studies to elucidate the mechanism of how E1A enhances chemosensitivity may provide a pathway to target that improves the likelihood of successfully treating breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2000
- Accession Number
- ADB266077
Entities
People
- Andrew V. Samuelson
- Scott W. Lowe
Organizations
- Cold Spring Harbor Laboratory