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PMID: 17322918 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

The Bcl-2 apoptotic switch in cancer development and therapy.

Oncogene ·Vol. 26 ·No. 9 ·2007-02-26 ·Pages 1324-37

Adams JM, Cory S

Abstract

Impaired apoptosis is both critical in cancer development and a major barrier to effective treatment. In response to diverse intracellular damage signals, including those evoked by cancer therapy, the cell's decision to undergo apoptosis is determined by interactions between three factions of the Bcl-2 protein family. The damage signals are transduced by the diverse 'BH3-only' proteins, distinguished by the BH3 domain used to engage their pro-survival relatives: Bcl-2, Bcl-x(L), Bcl-w, Mcl-1 and A1. This interaction ablates pro-survival function and allows activation of Bax and Bak, which commit the cell to apoptosis by permeabilizing the outer membrane of the mitochondrion. Certain BH3-only proteins (e.g. Bim, Puma) can engage all the pro-survival proteins, but others (e.g. Bad, Noxa) engage only subsets. Activation of Bax and Bak appears to require that the BH3-only proteins engage the multiple pro-survival proteins guarding Bax and Bak, rather than binding to the latter. The balance between the pro-survival proteins and their BH3 ligands regulates tissue homeostasis, and either overexpression of a pro-survival family member or loss of a proapoptotic relative can be oncogenic. Better understanding of the Bcl-2 family is clarifying its role in cancer development, revealing how conventional therapy works and stimulating the search for "BH3 mimetics" as a novel class of anticancer drugs.

MeSH Terms
Apoptosis/physiology Humans Molecular Mimicry Neoplasms/pathology,physiopathology,therapy Proto-Oncogene Proteins c-bcl-2/physiology
Chemicals
Proto-Oncogene Proteins c-bcl-2
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Adams J M
Department of Molecular Genetics of Cancer, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. adams@wehi.edu.au
Cory S
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Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
0950-9232
DOI
10.1038/sj.onc.1210220
Email
adams@wehi.edu.au
Published
2007-02-26
Pages
1324-37
Language
English
Region
England
NLM ID
8711562
PMCID
PMC2930981
Subset
IM
Grants
NCI NIH HHS · R01 CA043540-18 · United States
NCI NIH HHS · R01 CA043540 · United States
NCI NIH HHS · CA 43540 · United States
NCI NIH HHS · CA 80188 · United States
NCI NIH HHS · R01 CA080188 · United States
NCI NIH HHS · R01 CA080188-06 · United States
External Links
PubMed source DOI: 10.1038/sj.onc.1210220 PMC Full Text View journal details
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