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The Bcl2 family: regulators of the cellular life-or-death switch

Key Points

  • Apoptosis, the cell-death programme that is mediated by proteases called caspases, is essential for tissue homeostasis, and its perturbed regulation underlies many diseases, including cancer. Commitment to apoptosis in response to diverse physiological cues and cytotoxic agents is governed by proteins of the Bcl2 family.

  • Bcl2 and several pro-survival relatives associate with the mitochondrial outer membrane and the endoplasmic reticulum/nuclear membrane and maintain their integrity. Initiation of apoptosis requires not only pro-apoptotic family members such as Bax and Bak that closely resemble Bcl2, but also distant cousins that are related only by the small BH3 protein-interaction domain.

  • The BH3-only proteins are sentinels that detect developmental death cues or intracellular damage. In healthy cells, they are restrained in diverse ways, including sequestration on the cytoskeleton. When unleashed by death signals, they switch off survival function by inserting their BH3 domain into a groove on their pro-survival relatives.

  • Either Bax or Bak is required for apoptosis, but how they are activated or countermanded by Bcl2 remains uncertain. During apoptosis, Bax and Bak oligomerize in the mitochondrial outer membrane and probably breach its integrity, freeing pro-apoptotic proteins such as cytochrome c, which allows activation of caspase-9.

  • The pro-survival Bcl2-like proteins can prevent cytochrome c release, and hence caspase-9 activation. They probably also regulate the activation of several other caspases, independently of mitochondrial damage.

  • Impaired apoptosis is a central step towards neoplasia. Pro-survival Bcl2-like proteins can promote tumorigenesis, and certain pro-apoptotic relatives act as tumour suppressors. Moreover, the expression of family members is affected by other tumorigenic alterations (for example, p53 mutation).

  • Conventional cytotoxic therapy indirectly induces apoptosis, but more effective outcomes should be achieved by direct activation of the apoptotic machinery. Promising approaches include impairing expression of pro-survival Bcl2-like proteins or identifying drugs that mimic the action of BH3-only proteins.

Abstract

Tissue homeostasis is regulated by apoptosis, the cell-suicide programme that is executed by proteases called caspases. The Bcl2 family of intracellular proteins is the central regulator of caspase activation, and its opposing factions of anti- and pro-apoptotic members arbitrate the life-or-death decision. Apoptosis is often impaired in cancer and can limit conventional therapy. A better understanding of how the Bcl2 family controls caspase activation should result in new, more effective therapeutic approaches.

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Figure 1: Two main pathways to apoptosis.
Figure 2: Three subfamilies of Bcl2-related proteins.
Figure 3: Three-dimensional structures of Bcl-xL and Bax, showing their similarity.
Figure 4: Diverse modes of post-translational regulation of BH3-only proteins.
Figure 5: Two models for Bcl2 survival activity.
Figure 6: Caspase inhibitor model for Bcl2 function.

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Acknowledgements

Space limitations unfortunately precluded comprehensive referencing for all the work reviewed. We thank our institute colleagues, particularly A. Strasser, D. Huang and D.Vaux, for the many discussions that influenced this review. This work was supported in part by the National Health and Medical Research Council, by National Institutes of Health grants and by the Leukemia and Lymphoma Society (SCOR grant).

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Akt

Apaf1

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Arf

Bad

Bak

Bax

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BCL2

Bcl-w

Bcl-xL

Bid

Bim

Bmf

Bok

Boo

CARD

caspase-1 (mouse)

caspase -2 (mouse)

caspase-11 (mouse)

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caspase-1

caspase-2

caspase-3

caspase-4

caspase-5

caspase-6

caspase-7

caspase-8

caspase-9

caspase-10

Cdk4

Diablo/Smac

E2f1

endonuclease G

FADD

FAS

granzyme-B

Hrk

Mcl1

Mdm2

Myc

Noxa

Omi/HtrA2

p53

PML

Puma

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Rb

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TNF

TRAIL

Waf1

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EGL-1

Glossary

SCAFFOLD PROTEINS

Proteins that provide a platform for the assembly of other proteins.

ANOIKIS

Death promoted by detachment from the extracellular matrix.

WD40 REPEAT DOMAIN

A conserved protein domain that is approximately 40 residues long and that has a characteristic tryptophan–aspartate motif. In the case of the caspase-activator Apaf1, two groups of WD40 repeats in the carboxy-terminal region are thought to keep the protein inactive until cytochrome c engages the repeats.

RNA INTERFERENCE

A technique in which double-stranded RNA, or synthetic double-stranded RNA oligonucleotides about 21 nucleotides long, is used to silence expression of a gene of the same sequence. Ribonucleases in the cell use the introduced RNA as a guide to target and cleave the mRNA transcribed from that gene.

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Cory, S., Adams, J. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2, 647–656 (2002). https://doi.org/10.1038/nrc883

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