Identification and Characterization of Distinct Apoptotic Pathways in Cancer Cells Activated in Response to Treatment with Different Anti-Cancer Agents
Abstract
The adenovirus E1A oncoprotein sensitizes primary cells to undergo apoptosis following treatment with anticancer agents through a mechanism involving inactivation of the retinoblastoma (Rb) protein and stabilization of p53 tumor suppressor. Anticancer agents ultimately induce apoptosis by activating caspases, a family of cystein proteases that are essential components of the cell death machinery. Caspases are expressed as latent pro-enzymes and processed to active enzymes during apoptotic cell death. To further understand the mechanism whereby E1A promotes chemosensitivity, we examined pro-caspase levels in primary fibroblasts expressing E1A. Introduction of E1A greatly increased the levels of pro-caspases 2, 3, 7 and 8 through a post-transcriptional mechanism. The Rb binding domain of E1A is essential for pro-caspase induction, indicating that inactivation of Rb contributes to this effect. In contrast, the p53 and p19(ARF) tumor suppressors are dispensable for caspase induction, since E1A induces pro-caspase levels in p53-/- and ARF-/- MEFs. Nevertheless, the ability of E1A to induce pro-caspases and p53 may synergize to promote apoptosis. These studies provide a direct connection between a pro-apoptotic oncogene (E1A) and the cell death machinery. Caspase induction by E1A may contribute to its ability to promote chemosensitivity.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 1999
- Accession Number
- ADB257354
Entities
People
- Julia Polyakova
Organizations
- Cold Spring Harbor Laboratory