The role of the Bcl-2 protein family in cancer
Introduction
The bcl-2 gene family encodes a divergent group of proteins that regulate programmed cell death and stress-induced apoptosis by an evolutionarily conserved mechanism found in species as distantly related as humans and nematodes [1], [2], [3], [4]. One arm of this family, including mammalian Bcl-2, Bcl-xL, Bcl-w, A1, Mcl-1 and their C. elegans homologue CED-9, is required for cell survival [2], [5]. In contrast, two subgroups of the Bcl-2 family, including the Bax/Bak-like proteins [3], which are structurally remarkably similar to Bcl-2, as well as the more distantly related BH3-only proteins [6], are both required for apoptotic cell death. During embryogenesis, the Bcl-2 family controls developmentally programmed cell death that is involved in the sculpting of tissues, such as the formation of the nervous system and the digits [7]. After birth, Bcl-2 and its relatives play critical roles in regulating programmed cell death in the haematopoietic system, tissue homeostasis and mammary gland involution [7], [8]. In addition to regulating cell death triggered by developmental and physiological cues, members of the Bcl-2 protein family also control apoptosis induced by cytotoxic stress conditions, such as those elicited by anti-cancer drugs [2].
Abnormalities in cell death control can be a cause or contributing factor in a variety of diseases. For example, over-expression of the apoptosis inhibitor Bcl-2 or loss of its antagonist Bim can promote tumourigenesis [9], [10] or autoimmune disease [11], [12], [13]. Conversely, loss of Bcl-2 (or one of its homologues, e.g. Bcl-xL) can elicit degenerative diseases [14]. Interestingly, in the case of Bcl-2 deficiency all degenerative defects can be rescued by concomitant loss of its antagonist Bim [15].
Mammals have two distinct apoptosis signalling pathways [4]. The Bcl-2 protein family regulates cell death induced by certain developmental cues, cytokine withdrawal or cytotoxic stress conditions, but (in many cell types) it is not critical for apoptosis triggered by ‘death receptors’ (members of the tumour necrosis factor receptor—TNF-R—family with an intracellular death domain) [16], [17], [18]. Activation of pro-apoptotic Bcl-2 family members, most notably Bid, serves to amplify the apoptotic signal from ‘death receptors’, but in many cell types this appears to be dispensable for cell killing [3].
Not only defects in the Bcl-2-regulated apoptosis signalling pathway but also abnormalities in ‘death receptor’ signalling can cause disease [18]. For example, loss of function of Fas [19], [20], [21], its ligand, FasL [22], or its essential signal transducer FADD/MORT1 [23] can all cause lymphadenopathy, autoimmune disease and/or haematological malignancy.
Section snippets
Cell death signalling
Apoptotic cell death can be characterised morphologically and biochemically by blebbing of the plasma membrane, surface exposure of ‘eat me signals’, chromatin condensation, internucleosomal DNA cleavage and phagocytosis by neighbouring cells [24], [25]. These processes all depend on a family of aspartate-specific cysteine proteases (caspases) that cleave certain vital structural proteins (e.g. lamins, gelsolin) and proteolytically activate latent enzymes (e.g. nucleases) that contribute to
BH3-only proteins and Bax/Bak-like proteins are both essential for apoptosis
Gene knock-out studies in mice have shown that BH3-only proteins [6], [12] and Bax/Bak-like proteins [28] are both essential for programmed cell death and stress-induced apoptosis. Mice lacking Bax or Bak alone have only subtle or no phenotypic abnormalities but those lacking both proteins have developmental defects and the few animals that survive to adulthood develop lymphadenopathy [28]. Lymphocytes and fibroblasts from bax−/−bak−/− mice have similar resistance to a wide range of cytotoxic
The role of pro-survival Bcl-2 family members in tumourigenesis
The activities of Bcl-2 and its homologues have since their discovery been associated with cancer. The bcl-2 gene (B cell lymphoma gene-2) was the second gene identified as a transcriptional unit at the breakpoint of recurrent chromosomal translocation which is found in ∼85% of cases of human follicular centre lymphoma [60]. This chromosomal translocation results in deregulated high level expression of the bcl-2 gene in B lymphocytes as a consequence of its juxtaposition to the strong Eμ
The role of Bax/Bak-like pro-apoptotic proteins in tumourigenesis
Since over-expression of Bcl-2-like proteins promotes tumourigenesis, it is possible that pro-apoptotic Bcl-2 family members can function as tumour suppressors. Although bax−/− mice do not show marked predisposition to neoplasia [73], experiments in some mouse models of cancer development have suggested that Bax can function as a tumour suppressor [74], [75]. Loss of Bax was found to accelerate tumourigenesis in transgenic mice expressing a truncated version of the SV40 large T antigen that
The role of BH3-only proteins in tumourigenesis
It is noteworthy that Bax levels are elevated in tumours (compared to non-transformed cells) that form in transgenic mice expressing wild-type SV40 large T antigen and Bax levels are even elevated in tumours from those transgenic animals bred to a p53−/− background [75]. These findings demonstrate that while Bax is involved in p53-mediated apoptosis, Bax is not directly regulated by p53. This is contrary to a previous report which stated that p53 is a direct transcriptional activator of the bax
The role of Apaf-1 and caspase-9 in tumourigenesis
It is possible that effectors that are essential for apoptosis may function as tumour suppressors. Experiments with Apaf-1- or caspase-9-deficient mouse embryo fibroblasts have shown that upon c-myc over-expression these cells undergo less apoptosis and are more easily transformed than wild-type cells [80]. Since c-myc-induced apoptosis, which counter-balances its cell transformation potency [79], is p53 dependent (at least in some cell types) [79], it has been proposed that Apaf-1 and
The role of apoptosis and the Bcl-2 protein family in anti-cancer therapy
Radiation and many, possibly all, chemotherapeutic drugs trigger apoptosis in susceptible cells, both tumour-derived as well as normal ones. It is, however, controversial whether apoptosis sensitivity determines the outcome of treatment or whether it is only a consequence of the irreparable damage to vital processes sustained by the cell [81]. Experiments with normal lymphocytes and lymphomas have clearly demonstrated that Bcl-2 over-expression does not only inhibit radiation- and anti-cancer
Conclusions and perspectives
Abnormalities in cell death control are clearly implicated in the development of many, possibly all, types of cancers and may also play a role in rendering (at least some) tumours refractory to therapy. It will be interesting to find out from further genetic experiments with knock-out mice, which cell death regulators can function as oncogenes or tumour suppressors. Over-expression of Bcl-2 is only weakly oncogenic on its own but potently synergises with oncogenes that deregulate cell cycle
Acknowledgements
We wish to thank all of our past and present colleagues, particularly J. Adams, S. Cory, D. Vaux, D. Huang, H. Puthalakath, P. Bouillet, L. O’Reilly, A. Villunger, L. O’Connor, L. Tai, M. Pellegrini, K. Newton, V. Marsden, C. Scott, A. Harris, S. Bath and A. Egle for their help with our research and for discussions. Work in our laboratory is supported by grants and fellowships from the NHMRC (Canberra), the NIH, the Dr. Josef Steiner Cancer Research Foundation (Bern, Switzerland), the Leukaemia
References (83)
- et al.
BH3-only proteins—essential initiators of apoptotic cell death
Cell
(2000) - et al.
Programmed cell death in animal development
Cell
(1997) - et al.
Cell death control in lymphocytes
Adv. Immunol.
(2001) - et al.
Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair
Cell
(1993) - et al.
Degenerative disorders caused by Bcl-2 deficiency are prevented by loss of its BH3-only antagonist Bim
Dev. Cell
(2001) - et al.
Mice defective in two apoptosis pathways in the myeloid lineage develop acute myeloblastic leukemia
Immunity
(1998) - et al.
Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand
Cell
(1994) - et al.
Structure of Bax: coregulation of dimer formation and intracellular localization
Cell
(2000) - et al.
The combined functions of proapoptotic Bcl-2 family members Bak and Bax are essential for normal development of multiple tissues
Mol. Cell
(2000) - et al.
BCL-2, BCL-xL sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis
Mol. Cell
(2001)
The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9
Cell
Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria
J. Biol. Chem.
Activated T cell death in vivo mediated by pro-apoptotic Bcl-2 family member, Bim
Immunity
Bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship
Cell
bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes
Cell
Induction of Bim, a proapoptotic BH3-only Bcl-2 family member, is critical for neuronal apoptosis
Neuron
Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release
Neuron
PUMA induces the rapid apoptosis of colorectal cancer cells
Mol. Cell
PUMA, a novel proapoptotic gene, is induced by p53
Mol. Cell
Anoikis mechanisms
Curr. Opin. Cell Biol.
BH3-only Bcl-2 family members are coordinately regulated by the JNK pathway and require Bax to induce apoptosis in neurons
J. Biol. Chem.
Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not Bcl-xL
Cell
The pro-apoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex
Mol. Cell
Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis
Cell
Bid, a Bcl-2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors
Cell
bcl2 and v-abl oncogenes cooperate to immortalize murine B cells that secrete antigen specific antibodies
Immunol. Lett.
Peripheral T-cell lymphoma in lckpr-bcl-2 transgenic mice
Blood
MCL1 transgenic mice exhibit a high incidence of B-cell lymphoma manifested as a spectrum of histologic subtypes
Blood
p53, the cellular gatekeeper for growth and division
Cell
DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2
Cell
The molecular biology of apoptosis
Proc. Natl. Acad. Sci. U.S.A.
The Bcl-2 protein family: arbiters of cell survival
Science
Bcl-2 family members and the mitochondria in apoptosis
Genes Dev.
Apoptosis signaling
Annu. Rev. Biochem.
The biochemistry of apoptosis
Nature
Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells
Nature
Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2
Nature
Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease
Proc. Natl. Acad. Sci. U.S.A.
Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity
Science
BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes
Nature
Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis
EMBO J.
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