bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis

McCurrach, M. E., Connor, T. M., Knudson, C. M., Korsmeyer, S. J., Lowe, S. W. (March 1997) bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis. Proceedings of the National Academy of Sciences of the United States of America, 94 (6). pp. 2345-9. ISSN 0027-8424

URL: http://www.ncbi.nlm.nih.gov/pubmed/9122197

Abstract

Inactivation of p53-dependent apoptosis promotes oncogenic transformation, tumor development, and resistance to many cytotoxic anticancer agents. p53 can transcriptionally activate bax, a bcl-2 family member that promotes apoptosis. To determine whether bax is required for p53-dependent apoptosis, the effects of bax deficiency were examined in primary fibroblasts expressing the E1A oncogene, a setting where apoptosis is dependent on endogenous p53. We demonstrate that bax can function as an effector of p53 in chemotherapy-induced apoptosis and contributes to a p53 pathway to suppress oncogenic transformation. Furthermore, we show that additional p53 effectors participate in these processes. These p53-controlled factors act synergistically with Bax to promote a full apoptotic response, and their action is suppressed by the Bcl-2 and E1B 19K oncoproteins. These studies demonstrate that Bax is a determinant of p53-dependent chemosensitivity and illustrate how p53 can promote apoptosis by coordinating the activities of multiple effectors.

Item Type: Paper
Uncontrolled Keywords: Animals Apoptosis Cell Survival/drug effects Cell Transformation, Neoplastic Cells, Cultured Cisplatin/pharmacology Crosses, Genetic Doxorubicin/pharmacology Drug Resistance/ genetics Embryo Etoposide/pharmacology Fibroblasts Genes, p53 Mice Mice, Knockout Proto-Oncogene Proteins/ deficiency/genetics Proto-Oncogene Proteins c-bcl-2 RNA, Messenger/biosynthesis Recombination, Genetic Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Transcription, Genetic Tumor Suppressor Protein p53/biosynthesis/metabolism bcl-2-Associated X Protein
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis
organism description > animal > developmental stage > embryo
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > tumor suppressor
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: Kathleen Darby
Date: 18 March 1997
Date Deposited: 08 May 2014 14:58
Last Modified: 08 May 2014 16:14
PMCID: PMC20090
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29984

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