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Abstract
One of the most effective ways to combat different types of cancer is through early diagnosis and administration of effective treatment, followed by efficient monitoring that will allow physicians to detect relapsing disease and treat it at the earliest possible time. Apoptosis, a normal physiological form of cell death, is critically involved in the regulation of cellular homeostasis. Dysregulation of programmed cell death mechanisms plays an important role in the pathogenesis and progression of cancer as well as in the responses of tumours to therapeutic interventions.
Many members of the BCL2 (B-cell CLL/lymphoma 2; Bcl-2) family of apoptosis-related genes have been found to be differentially expressed in various malignancies, and some are useful prognostic cancer biomarkers. We have recently cloned a new member of this family, BCL2L12, which was found to be differentially expressed in many tumours. Most of the BCL2 family genes have been found to play a central regulatory role in apoptosis induction. Results have made it clear that a number of coordinating alterations in the BCL2 family of genes must occur to inhibit apoptosis and provoke carcinogenesis in a wide variety of cancers. However, more research is required to increase our understanding of the extent to which and the mechanisms by which they are involved in cancer development, providing the basis for earlier and more accurate cancer diagnosis, prognosis and therapeutic intervention that targets the apoptosis pathways.
In the present review, we describe current knowledge of the function and molecular characteristics of a series of classic but also newly discovered genes of the BCL2 family as well as their implications in cancer development, prognosis and treatment.
Key words :
- Apoptosis
- BCL2 gene family
- BCL-2
- BCL2L12
- cancer
- cancer prognosis
- cancer treatment
- tumour biomarkers
- BCL2L1
- MCL1
- BCL2L2
- BOO/DIVA
- BCL2A1
- BAX
- BAK1
- BOK
- BIK
- BID
- HRK
- BCL2L11
- BNIP
- BNIP1
- BNIP2
- BNIP3
- NIX
- ceBNIP3
- BLK
- PMAIP1
- BMF
- BBC3
- BCLAF1
- BCL2L13
- BCL2L14
- MAP-1
- BCL-B
- BCL2L10
- BFK
- AIDS
- Alzheimer
- Parkinson
- spinal muscular atrophy
- Hashimoto thyroiditis
- glomerulonephritis
- Emery-Dreifuss muscular dystrophy
| Abbreviations and Glossary | ||
| A549, | = | lung cancer cells; |
| AD, | = | Alzheimer's disease; |
| AIDS, | = | acquired immunodeficiency syndrome; |
| Akt, | = | protein kinase B; |
| ALL, | = | acute lymphocytic leukemia; |
| AML, | = | acute myeloid leukemia; |
| ANT, | = | adenine nucleotide transporter; |
| Apaf1, | = | apoptosis-activating factor 1; |
| ATLL, | = | acute T lymphocytic leukemia; |
| BAD, | = | BCL2-antagonist of cell death; |
| BAF-3, | = | human bone marrow-derived cells; |
| BAK1, | = | BCL2-antagonist/killer 1; |
| BAX, | = | BCL2-associated X protein; |
| BBC3, | = | BCL2 binding component 3; |
| B-CLL, | = | B-cell chronic lymphocytic leukemia; |
| BCL2, | = | B-cell CLL/lymphoma 2; |
| BCL2L1, | = | BCL2-like protein 1; |
| BCL2L10, | = | BCL2-like protein 10; |
| BCL-Xγ, | = | BCL-X gamma form; |
| BCL-XL, | = | BCL-X long form; |
| BCL-XS, | = | BCL-X short form; |
| BCR/ABL, | = | breakpoint cluster region/Abelson leukemia; |
| BFL1S, | = | BFL short form; |
| BH, | = | BCL2 homology region; |
| BHRF-1, | = | Epstein-Barr virus BCL2 homologue; |
| BID, | = | BH3-interacting domain agonist; |
| BIK, | = | BCL2-interacting killer; |
| BIM, | = | BCL2-interacting mediator; |
| BMF, | = | BCL2-modifying factor; |
| BNIP, | = | BCL2 and the nineteen kDa interacting protein; |
| BOK, | = | BCL2-related ovarian killer; |
| BOKS, | = | BOK short form; |
| BOO, | = | BCL2 homologue of the ovary; |
| BTF, | = | BCL2-associated transcription factor; |
| BTFL, | = | BTF long form; |
| BTFS, | = | BTF short form; |
| CD, | = | conserved domain; |
| CD40, | = | cluster of differentiation 40; |
| CD40L, | = | CD40 ligand; |
| ceBNIP3, | = | C. elegans BNIP3; |
| CED, | = | cell death protein; |
| CGH, | = | comparative genomic hybridization; |
| CMML, | = | chronic myelomonocytic leukemia; |
| CPP32, | = | cysteine protease protein of molecular mass 32 kDa; |
| CPT, | = | camptothecin; |
| CVB3, | = | coxackievirus B3; |
| CWR22, | = | human prostate cancer xenograft; |
| DA, | = | dopaminergic neurons; |
| DCM, | = | dilated cardiomyopathy; |
| DIVA, | = | death inducer binding to vBCL2 and apoptosis-activating factor, APAF-1; |
| DLC, | = | dynein light chain; |
| DREAM, | = | downstream regulatory element antagonist modulator; |
| DS, | = | Down syndrome; |
| DT40, | = | bursal lymphoma cell line; |
| EDMD, | = | Emery-Dreifuss muscular dystrophy; |
| EGF, | = | epidermal growth factor; |
| ER, | = | endoplasmic reticulum; |
| ERK, | = | extracellular signal-regulated kinase; |
| FasL, | = | Fas-ligand; |
| FDC-P1, | = | mouse promyelocytic cells; |
| FSH, | = | follicle-stimulating hormone; |
| GAP, | = | GTPase-activating protein; |
| GBM, | = | glioblastoma multiform; |
| G-CSF, | = | granulocyte colony-stimulating factor; |
| GM-CSF, | = | granulocyte macrophage colony-stimulating factor; |
| GTN, | = | gestational trophoblastic neoplasia; |
| HCC-T, | = | hepatocellular carcinoma; |
| HeLa, | = | human cervix carcinoma epithelial cells; |
| HL-CR, | = | ceramide resistant HL-60 subline; |
| HM, | = | hydatidiform mole; |
| HNSCC, | = | head/neck squamous cell carcinoma; |
| HPV, | = | human papillovirus; |
| HRK, | = | Harakiri; |
| HTLV, | = | human T lymphotropic virus; |
| IAPs, | = | inhibitors of apoptosis; |
| IGF-1, | = | insulin-like growth factor-1; |
| JAK, | = | Janus kinase; |
| JNK, | = | c-Jun NH2-terminal kinase; |
| IFN-α, | = | interferon-alpha; |
| IL, | = | interleukin; |
| IRF3, | = | interferon regulatory factor 3; |
| JHU, | = | head/neck cancer cells; |
| K562/AC, | = | K562 cell line Ara-C resistant; |
| KLK, | = | kallikrein; |
| L929, | = | mouse fibroblasts; |
| LNCaP, | = | prostatic carcinoma cell line; |
| LOH, | = | loss of heterozygosity; |
| LPS, | = | lipopolysaccharide; |
| MA, | = | membrane anchor; |
| MAP, | = | mitogen-activated protein; |
| MAP-1, | = | modulator of apoptosis-1; |
| MAPK1, | = | MAP kinase 1; |
| MCL1, | = | myeloid cell leukemia 1; |
| MCL1L, | = | MCL1 long form; |
| MCL1S, | = | MCL1 short form; |
| MCF-7, | = | human epithelial breast cancer cells; |
| MEK, | = | MAPK/ERK kinase; |
| Met, | = | a proto-oncogene encoding the tyrosine kinase growth factor receptor for hepatocyte growth factor; |
| ML-1, | = | human myeloblastic leukaemia cells; |
| MM, | = | malignant melanoma; |
| MMP, | = | mitochondrial membrane potential; |
| NF-κ B, | = | nuclear factor-kappa B; |
| NGF, | = | nerve growth factor; |
| NLS, | = | nuclear localization signal; |
| NOD, | = | non-obese diabetic; |
| NOXA, | = | a proapoptotic BH3-only member of the BCL2 protein family; |
| PAK, | = | p21-activated kinase; |
| PEST, | = | sequence enriched in proline/glutamic acid/serine/threonine; |
| PDGF, | = | platelet-derived growth factor; |
| PI3K, | = | phosphatidylinositol 3-kinase; |
| PKA, | = | protein kinase A; |
| PLFZ, | = | promyelocytic leukaemia zinc-finger gene; |
| PMA, | = | phorbol ester; |
| PT, | = | permeability transition; |
| PTP, | = | permeability transition pore; |
| PUMA, | = | p53-up-regulated modulator of apoptosis; |
| Raf, | = | oncogene; |
| Ras, | = | oncogene; |
| ROS, | = | reactive oxygen species; |
| RRAS, | = | Ras-related protein R-Ras; |
| RSK, | = | ribosomal S6 kinase; |
| RT-PCR, | = | reverse transcription-polymerase chain reaction; |
| Saos2, | = | human osteosarcoma cells; |
| SH3, | = | src homology 3; |
| SH-SY5Y, | = | human neuroblastoma cells; |
| SLE, | = | systemic lupus erythematosus; |
| SRF, | = | serum factor; |
| SSCP, | = | single-strand conformation polymorphism; |
| STAT3, | = | signal transducers and activators of transcription; |
| tBAD, | = | truncated BAD; |
| tBID, | = | truncated BID; |
| TCC, | = | transitional cell carcinoma; |
| TF1, | = | myeloid progenitor cell line; |
| TM, | = | transmembrane; |
| TNF, | = | tumour necrosis factor; |
| TRAIL, | = | tumour necrosis factor-related apoptosis-inducing ligand; |
| Ubi-L, | = | ubiquitin-like; |
| U87, | = | human glioblastoma cells; |
| U251, | = | human glioblastoma cells; |
| U138, | = | human glioblastoma cells; |
| VDAC, | = | voltage-dependent anion channels; |
| VEGF, | = | vascular endothelial growth factor; |
| WT, | = | wild type. |
| Abbreviations and Glossary | ||
| A549, | = | lung cancer cells; |
| AD, | = | Alzheimer's disease; |
| AIDS, | = | acquired immunodeficiency syndrome; |
| Akt, | = | protein kinase B; |
| ALL, | = | acute lymphocytic leukemia; |
| AML, | = | acute myeloid leukemia; |
| ANT, | = | adenine nucleotide transporter; |
| Apaf1, | = | apoptosis-activating factor 1; |
| ATLL, | = | acute T lymphocytic leukemia; |
| BAD, | = | BCL2-antagonist of cell death; |
| BAF-3, | = | human bone marrow-derived cells; |
| BAK1, | = | BCL2-antagonist/killer 1; |
| BAX, | = | BCL2-associated X protein; |
| BBC3, | = | BCL2 binding component 3; |
| B-CLL, | = | B-cell chronic lymphocytic leukemia; |
| BCL2, | = | B-cell CLL/lymphoma 2; |
| BCL2L1, | = | BCL2-like protein 1; |
| BCL2L10, | = | BCL2-like protein 10; |
| BCL-Xγ, | = | BCL-X gamma form; |
| BCL-XL, | = | BCL-X long form; |
| BCL-XS, | = | BCL-X short form; |
| BCR/ABL, | = | breakpoint cluster region/Abelson leukemia; |
| BFL1S, | = | BFL short form; |
| BH, | = | BCL2 homology region; |
| BHRF-1, | = | Epstein-Barr virus BCL2 homologue; |
| BID, | = | BH3-interacting domain agonist; |
| BIK, | = | BCL2-interacting killer; |
| BIM, | = | BCL2-interacting mediator; |
| BMF, | = | BCL2-modifying factor; |
| BNIP, | = | BCL2 and the nineteen kDa interacting protein; |
| BOK, | = | BCL2-related ovarian killer; |
| BOKS, | = | BOK short form; |
| BOO, | = | BCL2 homologue of the ovary; |
| BTF, | = | BCL2-associated transcription factor; |
| BTFL, | = | BTF long form; |
| BTFS, | = | BTF short form; |
| CD, | = | conserved domain; |
| CD40, | = | cluster of differentiation 40; |
| CD40L, | = | CD40 ligand; |
| ceBNIP3, | = | C. elegans BNIP3; |
| CED, | = | cell death protein; |
| CGH, | = | comparative genomic hybridization; |
| CMML, | = | chronic myelomonocytic leukemia; |
| CPP32, | = | cysteine protease protein of molecular mass 32 kDa; |
| CPT, | = | camptothecin; |
| CVB3, | = | coxackievirus B3; |
| CWR22, | = | human prostate cancer xenograft; |
| DA, | = | dopaminergic neurons; |
| DCM, | = | dilated cardiomyopathy; |
| DIVA, | = | death inducer binding to vBCL2 and apoptosis-activating factor, APAF-1; |
| DLC, | = | dynein light chain; |
| DREAM, | = | downstream regulatory element antagonist modulator; |
| DS, | = | Down syndrome; |
| DT40, | = | bursal lymphoma cell line; |
| EDMD, | = | Emery-Dreifuss muscular dystrophy; |
| EGF, | = | epidermal growth factor; |
| ER, | = | endoplasmic reticulum; |
| ERK, | = | extracellular signal-regulated kinase; |
| FasL, | = | Fas-ligand; |
| FDC-P1, | = | mouse promyelocytic cells; |
| FSH, | = | follicle-stimulating hormone; |
| GAP, | = | GTPase-activating protein; |
| GBM, | = | glioblastoma multiform; |
| G-CSF, | = | granulocyte colony-stimulating factor; |
| GM-CSF, | = | granulocyte macrophage colony-stimulating factor; |
| GTN, | = | gestational trophoblastic neoplasia; |
| HCC-T, | = | hepatocellular carcinoma; |
| HeLa, | = | human cervix carcinoma epithelial cells; |
| HL-CR, | = | ceramide resistant HL-60 subline; |
| HM, | = | hydatidiform mole; |
| HNSCC, | = | head/neck squamous cell carcinoma; |
| HPV, | = | human papillovirus; |
| HRK, | = | Harakiri; |
| HTLV, | = | human T lymphotropic virus; |
| IAPs, | = | inhibitors of apoptosis; |
| IGF-1, | = | insulin-like growth factor-1; |
| JAK, | = | Janus kinase; |
| JNK, | = | c-Jun NH2-terminal kinase; |
| IFN-α, | = | interferon-alpha; |
| IL, | = | interleukin; |
| IRF3, | = | interferon regulatory factor 3; |
| JHU, | = | head/neck cancer cells; |
| K562/AC, | = | K562 cell line Ara-C resistant; |
| KLK, | = | kallikrein; |
| L929, | = | mouse fibroblasts; |
| LNCaP, | = | prostatic carcinoma cell line; |
| LOH, | = | loss of heterozygosity; |
| LPS, | = | lipopolysaccharide; |
| MA, | = | membrane anchor; |
| MAP, | = | mitogen-activated protein; |
| MAP-1, | = | modulator of apoptosis-1; |
| MAPK1, | = | MAP kinase 1; |
| MCL1, | = | myeloid cell leukemia 1; |
| MCL1L, | = | MCL1 long form; |
| MCL1S, | = | MCL1 short form; |
| MCF-7, | = | human epithelial breast cancer cells; |
| MEK, | = | MAPK/ERK kinase; |
| Met, | = | a proto-oncogene encoding the tyrosine kinase growth factor receptor for hepatocyte growth factor; |
| ML-1, | = | human myeloblastic leukaemia cells; |
| MM, | = | malignant melanoma; |
| MMP, | = | mitochondrial membrane potential; |
| NF-κ B, | = | nuclear factor-kappa B; |
| NGF, | = | nerve growth factor; |
| NLS, | = | nuclear localization signal; |
| NOD, | = | non-obese diabetic; |
| NOXA, | = | a proapoptotic BH3-only member of the BCL2 protein family; |
| PAK, | = | p21-activated kinase; |
| PEST, | = | sequence enriched in proline/glutamic acid/serine/threonine; |
| PDGF, | = | platelet-derived growth factor; |
| PI3K, | = | phosphatidylinositol 3-kinase; |
| PKA, | = | protein kinase A; |
| PLFZ, | = | promyelocytic leukaemia zinc-finger gene; |
| PMA, | = | phorbol ester; |
| PT, | = | permeability transition; |
| PTP, | = | permeability transition pore; |
| PUMA, | = | p53-up-regulated modulator of apoptosis; |
| Raf, | = | oncogene; |
| Ras, | = | oncogene; |
| ROS, | = | reactive oxygen species; |
| RRAS, | = | Ras-related protein R-Ras; |
| RSK, | = | ribosomal S6 kinase; |
| RT-PCR, | = | reverse transcription-polymerase chain reaction; |
| Saos2, | = | human osteosarcoma cells; |
| SH3, | = | src homology 3; |
| SH-SY5Y, | = | human neuroblastoma cells; |
| SLE, | = | systemic lupus erythematosus; |
| SRF, | = | serum factor; |
| SSCP, | = | single-strand conformation polymorphism; |
| STAT3, | = | signal transducers and activators of transcription; |
| tBAD, | = | truncated BAD; |
| tBID, | = | truncated BID; |
| TCC, | = | transitional cell carcinoma; |
| TF1, | = | myeloid progenitor cell line; |
| TM, | = | transmembrane; |
| TNF, | = | tumour necrosis factor; |
| TRAIL, | = | tumour necrosis factor-related apoptosis-inducing ligand; |
| Ubi-L, | = | ubiquitin-like; |
| U87, | = | human glioblastoma cells; |
| U251, | = | human glioblastoma cells; |
| U138, | = | human glioblastoma cells; |
| VDAC, | = | voltage-dependent anion channels; |
| VEGF, | = | vascular endothelial growth factor; |
| WT, | = | wild type. |