Oncogene-dependent apoptosis in extracts from drug-resistant cells

Fearnhead, H. O., McCurrach, M. E., O'Neill, J., Zhang, K., Lowe, S. W., Lazebnik, Y. A. (1997) Oncogene-dependent apoptosis in extracts from drug-resistant cells. Genes Dev, 11 (10). pp. 1266-1276. ISSN 0890-9369

[img]
Preview
PDF (Paper)
Lazebnik Genes & Dev 1997.full.pdf - Published Version

Download (3621Kb) | Preview
URL: http://www.ncbi.nlm.nih.gov/pubmed/9171371
DOI: 10.1101/gad.11.10.1266

Abstract

Many genotoxic agents kill tumor cells by inducing apoptosis; hence, mutations that suppress apoptosis produce resistance to chemotherapy. Although directly activating the apoptotic machinery may bypass these mutations, how to achieve this activation in cancer cells selectively is not clear. In this study, we show that the drug-resistant 293 cell line is unable to activate components of the apoptotic machinery-the ICE-like proteases (caspases)-following treatment with an anticancer drug. Remarkably, extracts from untreated cells spontaneously activate caspases and induce apoptosis in a cell-free system, indicating that drug-resistant cells have not only the apoptotic machinery but also its activator. Comparing extracts from cells with defined genetic differences, we show that this activator is generated by the adenovirus E1A oncogene and is absent from normal cells. We provide preliminary characterization of this oncogene generated activity (OGA) and show that partially purified OGA activates caspases when added to extracts from untransformed cells. We suggest that agents that link OGA to caspases in cells would kill tumor cells otherwise resistant to conventional cancer therapy. As this killing relies on an activity generated by an oncogene, the effect of these agents should be selective for transformed cells.

Item Type: Paper
Uncontrolled Keywords: Adenosine Triphosphate Adenovirus E1A Proteins Adenovirus E2 Proteins Apoptosis Cell Line Cell-Free System Chromatography, Ion Exchange Cysteine Endopeptidases Drug Resistance, Multiple Enzyme Activation Genes, bcl-2 HeLa Cells Humans Hydrolysis Oncogenes
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
CSHL Authors:
Communities: CSHL labs > Labeznik lab
CSHL labs > Lowe lab
Depositing User: Matt Covey
Date: 1997
Date Deposited: 12 Dec 2012 17:30
Last Modified: 12 Dec 2012 17:30
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26399

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving