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

Mila E McCurrach; Thomas M. F Connor; C. Michael Knudson; Stanley J Korsmeyer; Scott W Lowe

doi:10.1073/pnas.94.6.2345

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

Journal article

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

Mila E McCurrach, Thomas M. F Connor, C. Michael Knudson, Stanley J Korsmeyer and Scott W Lowe

Proceedings of the National Academy of Sciences - PNAS, Vol.94(6), pp.2345-2349

03/18/1997

DOI: 10.1073/pnas.94.6.2345

PMCID: PMC20090

PMID: 9122197

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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.

Biological Sciences

Details

Title: Subtitle: bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis
Creators: Mila E McCurrach - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724; and
Thomas M. F Connor - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724; and
C. Michael Knudson - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724; and
Stanley J Korsmeyer - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724; and
Scott W Lowe - Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724; and
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.94(6), pp.2345-2349
DOI: 10.1073/pnas.94.6.2345
PMID: 9122197
PMCID: PMC20090
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Language: English
Date published: 03/18/1997
Academic Unit: Pathology; Radiation Oncology
Record Identifier: 9984046828502771

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