B-cell CLL/lymphoma 2 |
PDB rendering based on 1GJH,1G5M. |
Available structures |
PDB |
Ortholog search: PDBe, RCSB |
List of PDB id codes |
1G5M, 1GJH, 1YSW, 2O21, 2O22, 2O2F, 2W3L, 2XA0, 4AQ3, 4IEH, 4LVT, 4LXD, 4LXE
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Identifiers |
Symbols |
BCL2 ; Bcl-2; PPP1R50 |
External IDs |
OMIM: 151430 MGI: 88138 HomoloGene: 527 ChEMBL: 4860 GeneCards: BCL2 Gene |
Gene ontology |
Molecular function |
• protease binding
• protein binding
• transcription factor binding
• channel activity
• ubiquitin protein ligase binding
• identical protein binding
• protein homodimerization activity
• sequence-specific DNA binding
• protein heterodimerization activity
• BH3 domain binding
• protein phosphatase 2A binding
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Cellular component |
• nucleus
• cytoplasm
• mitochondrion
• mitochondrial outer membrane
• endoplasmic reticulum
• endoplasmic reticulum membrane
• cytosol
• membrane
• nuclear membrane
• myelin sheath
• pore complex
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Biological process |
• G1/S transition of mitotic cell cycle
• protein polyubiquitination
• response to acid
• ossification
• ovarian follicle development
• metanephros development
• branching involved in ureteric bud morphogenesis
• behavioral fear response
• B cell homeostasis
• release of cytochrome c from mitochondria
• regulation of cell-matrix adhesion
• lymphoid progenitor cell differentiation
• B cell lineage commitment
• renal system process
• protein dephosphorylation
• melanin metabolic process
• regulation of nitrogen utilization
• apoptotic process
• humoral immune response
• response to DNA damage stimulus
• actin filament organization
• female pregnancy
• cell aging
• cell death
• male gonad development
• response to radiation
• response to external stimulus
• response to toxic substance
• post-embryonic development
• response to iron ion
• response to UV-B
• response to gamma radiation
• negative regulation of autophagy
• negative regulation of calcium ion transport into cytosol
• regulation of glycoprotein biosynthetic process
• mesenchymal cell development
• positive regulation of neuron maturation
• positive regulation of smooth muscle cell migration
• cell growth
• cell-cell adhesion
• peptidyl-serine phosphorylation
• peptidyl-threonine phosphorylation
• cochlear nucleus development
• gland morphogenesis
• regulation of transmembrane transporter activity
• negative regulation of ossification
• positive regulation of cell growth
• negative regulation of cell growth
• melanocyte differentiation
• negative regulation of cell migration
• positive regulation of B cell proliferation
• hair follicle morphogenesis
• axon regeneration
• regulation of protein stability
• endoplasmic reticulum calcium ion homeostasis
• glomerulus development
• negative regulation of cellular pH reduction
• negative regulation of myeloid cell apoptotic process
• T cell differentiation in thymus
• positive regulation of peptidyl-serine phosphorylation
• negative regulation of osteoblast proliferation
• response to cytokine stimulus
• response to nicotine
• organ growth
• nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway
• positive regulation of multicellular organism growth
• B cell proliferation
• response to drug
• response to hydrogen peroxide
• T cell homeostasis
• negative regulation of apoptotic process
• positive regulation of catalytic activity
• CD8-positive, alpha-beta T cell lineage commitment
• regulation of protein homodimerization activity
• regulation of protein heterodimerization activity
• negative regulation of neuron apoptotic process
• ear development
• regulation of viral genome replication
• innate immune response
• positive regulation of melanocyte differentiation
• negative regulation of mitotic cell cycle
• negative regulation of retinal cell programmed cell death
• regulation of mitochondrial membrane permeability
• focal adhesion assembly
• spleen development
• thymus development
• digestive tract morphogenesis
• developmental growth
• oocyte development
• positive regulation of skeletal muscle fiber development
• pigment granule organization
• homeostasis of number of cells within a tissue
• B cell receptor signaling pathway
• response to glucocorticoid stimulus
• neuron apoptotic process
• defense response to virus
• regulation of mitochondrial membrane potential
• negative regulation of mitochondrial depolarization
• regulation of calcium ion transport
• intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
• cellular response to organic substance
• reactive oxygen species metabolic process
• intrinsic apoptotic signaling pathway
• positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway
• negative regulation of anoikis
• negative regulation of apoptotic signaling pathway
• positive regulation of intrinsic apoptotic signaling pathway
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Sources: Amigo / QuickGO |
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RNA expression pattern |
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More reference expression data |
Orthologs |
Species |
Human |
Mouse |
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Entrez |
596 |
12043 |
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Ensembl |
ENSG00000171791 |
ENSMUSG00000057329 |
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UniProt |
P10415 |
P10417 |
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RefSeq (mRNA) |
NM_000633 |
NM_009741 |
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RefSeq (protein) |
NP_000624 |
NP_033871 |
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Location (UCSC) |
Chr 18:
60.79 – 60.99 Mb |
Chr 1:
106.54 – 106.71 Mb |
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PubMed search |
[1] |
[2] |
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Bcl-2 (B-cell lymphoma 2), encoded in humans by the BCL2 gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inducing (pro-apoptotic) it or inhibiting it (anti-apoptotic).[1][2] Bcl-2 is specifically considered as an important anti-apoptotic protein and is thus classified as an oncogene.
Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in follicular lymphomas. Orthologs[3] (such as Bcl2 in mice) have been identified in numerous mammals for which complete genome data are available. The two isoforms of Bcl-2, Isoform 1, also known as 1G5M, and Isoform 2, also known as 1G5O/1GJH, exhibit similar fold. However, results in the ability of these isoforms to bind to the BAD and BAK proteins, as well as in the structural topology and electrostatic potential of the binding groove, suggest differences in antiapoptotic activity for the two isoforms [4]
Like BCL3, BCL5, BCL6, BCL7A, BCL9, and BCL10, it has clinical significance in lymphoma.
Contents
- 1 Role in disease
- 2 Targeted therapies
- 2.1 Genasense
- 2.2 ABT-737
- 2.3 ABT-199
- 2.4 Others
- 3 Interactions
- 4 Human BCL-2 genes
- 5 See also
- 6 References
- 7 External links
Role in disease
Damage to the Bcl-2 gene has been identified as a cause of a number of cancers, including melanoma, breast, prostate, chronic lymphocytic leukemia, and lung cancer, and a possible cause of schizophrenia and autoimmunity. It is also a cause of resistance to cancer treatments.
Cancer occurs as the result of a disturbance in the homeostatic balance between cell growth and cell death. Over-expression of anti-apoptotic genes, and under-expression of pro-apoptotic genes, can result in the lack of cell death that is characteristic of cancer. An example can be seen in lymphomas. The over-expression of the anti-apoptotic Bcl-2 protein in lymphocytes alone does not cause cancer. But simultaneous over-expression of Bcl-2 and the proto-oncogene myc may produce aggressive B-cell malignancies including lymphoma.[5] In follicular lymphoma, a chromosomal translocation commonly occurs between the fourteenth and the eighteenth chromosomes—t(14;18) — which places the Bcl-2 gene next to the immunoglobulin heavy chain locus. This fusion gene is deregulated, leading to the transcription of excessively high levels of Bcl-2.[6] This decreases the propensity of these cells for undergoing apoptosis.
Apoptosis also plays a very active role in regulating the immune system. When it is functional, it can cause immune unresponsiveness to self-antigens via both central and peripheral tolerance. In the case of defective apoptosis, it may contribute to etiological aspects of autoimmune diseases.[7] The autoimmune disease, type 1 diabetes can be caused by defective apoptosis, which leads to aberrant T cell AICD and defective peripheral tolerance. Due to the fact that dendritic cells are the most important antigen-presenting cells of the immune system, their activity must be tightly regulated by such mechanisms as apoptosis. Researchers have found that mice containing dendritic cells that are Bim -/-, thus unable to induce effective apoptosis, obtain autoimmune diseases more so than those that have normal dendritic cells.[7] Other studies have shown that the lifespan of dendritic cells may be partly controlled by a timer dependent on anti-apoptotic Bcl-2.[7]
Apoptosis plays a very important role in regulating a variety of diseases that have enormous social impacts. For example, schizophrenia is a neurodegenerative disease that may result from an abnormal ratio of pro- and anti-apoptotic factors.[8] There is some evidence that this defective apoptosis may result from abnormal expression of Bcl-2 and increased expression of caspase-3.[8]
Further research into the family of Bcl-2 proteins will provide a more complete picture on how these proteins interact with each other to promote and inhibit apoptosis.[citation needed] An understanding of the mechanisms involved may help develop new therapies for treating cancer, autoimmune conditions, and neurological diseases.
Diagnostic use
Antibodies to Bcl-2 can be used with immunohistochemistry to identify cells containing the antigen. In healthy tissue, these antibodies will react with B-cells in the mantle zone, as well as some T-cells. However, there is a considerable increase in positive cells in follicular lymphoma, as well as many other forms of cancer. In some cases, the presence or absence of Bcl-2 staining in biopsies may be significant for the patient's prognosis or likelihood of relapse.[9]
Targeted therapies
Bcl-2 inhibitors include :
Genasense
An antisense oligonucleotide drug Genasense (G3139) has been developed by Genta Incorporated to target Bcl-2. An antisense DNA or RNA strand is non-coding and complementary to the coding strand (which is the template for producing respectively RNA or protein). An antisense drug is a short sequence of RNA that hybridises with and inactivates mRNA, preventing the protein from being formed.
It was shown that the proliferation of human lymphoma cells (with t(14;18) translocation) could be inhibited by antisense RNA targeted at the start codon region of Bcl-2 mRNA. In vitro studies led to the identification of Genasense, which is complementary to the first 6 codons of Bcl-2 mRNA.[10]
These have shown successful results in Phase I/II trials for lymphoma, and a large Phase III trial was launched in 2004[11]
By the first quarter 2010, Genasense had not received FDA approval due to disappointing results in a melanoma trial. Although safety and efficacy of Genasense have not been established for any use, Genta Incorporated still claims on its website that studies are currently underway to examine the potential role of Genasense in a variety of clinical indications.
ABT-737
In the mid-2000s, Abbott Laboratories developed a novel inhibitor of Bcl-2, Bcl-xL, and Bcl-w, known as ABT-737. This compound is part of a group of BH3 mimetic small molecule inhibitors (SMI), which target these Bcl-2 family proteins, but not A1 or Mcl-1. ABT-737 is superior to previous BCL-2 inhibitors because this compound has higher affinity for Bcl-2, Bcl-xL, and Bcl-w. In in vitro studies, primary cells from patients with B-cell malignancies are extremely sensitive to ABT-737.[12] ABT-737 does not directly induce apoptosis; it enhances the effects of the death signals and causes single-agent-mechanism-based killing of cells in small-cell lung carcinoma and lymphoma lines. In animal models, it improves survival, causes tumor regression, and results in the cure of a high percentage of mice.[13] Finally, in preclinical studies utilizing patient xenografts, ABT-737 has shown efficacy for treating lymphoma and other blood cancers.[14]
ABT-199
A Phase Ia trial is currently ongoing to study the effects of agent ABT-199, a so-called BH3-mimetic drug designed to block the function of the Bcl-2 protein, on patients with chronic lymphocytic leukemia.[15] Some very good responses have been reported.[16]
Others
- obatoclax (GX15-070) has phase II results for small-cell lung cancer.[17]
Interactions
Overview of signal transduction pathways involved in apoptosis.
Bcl-2 has been shown to interact with:
- BAK1,[18][19]
- BCAP31,[20]
- BCL2-like 1,[18][21]
- BCL2L11,[22][23][24]
- BECN1,[25]
- BID,[22][26]
- BMF,[27]
- BNIP2,[28][29]
- BNIP3,[29][30]
- BNIPL,[28][31]
- BAD[22][32]
- BAX,[33][18][34][35]
- BIK,[22][36]
- C-Raf,[37]
- CAPN2,[38]
- CASP8,[39][40]
- Cdk1,[41][42]
- HRK,[22][43]
- IRS1,[44]
- Myc,[45]
- NR4A1,[18]
- Noxa,[22][46]
- PPP2CA,[47]
- PSEN1,[48]
- RAD9A,[33]
- RRAS,[49]
- RTN4,[50]
- SMN1,[51]
- SOD1,[52] and
- TP53BP2.[53]
Human BCL-2 genes
BAK; BAK1; BAX; BCL2; BCL2A1; BCL2L1; BCL2L10; BCL2L13; BCL2L14; BCL2L2; BCL2L7P1; BOK; MCL1; LGALS7 (Galectin-7)
See also
- Apoptosis
- Apoptosome
- Bcl-2 homologous antagonist killer (BAK)
- Bcl-2-associated X protein (BAX)
- BH3 interacting domain death agonist (BID)
- Caspases
- Cytochrome c
- Noxa
- Mitochondrion
- Microphthalmia-associated transcription factor
- p53 upregulated modulator of apoptosis (PUMA)
References
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- ^ Cleary ML, Smith SD, Sklar J (October 1986). "Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation". Cell 47 (1): 19–28. doi:10.1016/0092-8674(86)90362-4. PMID 2875799.
- ^ "OrthoMaM phylogenetic marker: Bcl-2 coding sequence".
- ^ "Human Bcl2, Isoform 1".
- ^ Otake Y, Soundararajan S, Sengupta TK, Kio EA, Smith JC, Pineda-Roman M, Stuart RK, Spicer EK, Fernandes DJ (April 2007). "Overexpression of nucleolin in chronic lymphocytic leukemia cells induces stabilization of bcl2 mRNA". Blood 109 (7): 3069–75. doi:10.1182/blood-2006-08-043257. PMC 1852223. PMID 17179226.
- ^ Vaux DL, Cory S, Adams JM (September 1988). "Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells". Nature 335 (6189): 440–2. doi:10.1038/335440a0. PMID 3262202.
- ^ a b c Li A, Ojogho O, Escher A (2006). "Saving death: apoptosis for intervention in transplantation and autoimmunity". Clin. Dev. Immunol. 13 (2–4): 273–82. doi:10.1080/17402520600834704. PMC 2270759. PMID 17162368.
- ^ a b Glantz LA, Gilmore JH, Lieberman JA, Jarskog LF (January 2006). "Apoptotic mechanisms and the synaptic pathology of schizophrenia". Schizophr. Res. 81 (1): 47–63. doi:10.1016/j.schres.2005.08.014. PMID 16226876.
- ^ Leong, Anthony S-Y; Cooper, Kumarason; Leong, F Joel W-M (2003). Manual of Diagnostic Cytology (2 ed.). Greenwich Medical Media, Ltd. pp. XX. ISBN 1-84110-100-1.
- ^ Dias N, Stein CA (November 2002). "Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides". Eur J Pharm Biopharm 54 (3): 263–9. doi:10.1016/S0939-6411(02)00060-7. PMID 12445555.
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- ^ Vogler, Meike, et al. "Bcl-2 inhibitors: small molecules with a big impact on cancer therapy." Cell Death & Differentiation 16.3 (2008): 360-367.
- ^ Oltersdorf, Tilman, et al. "An inhibitor of Bcl-2 family proteins induces regression of solid tumours." Nature 435.7042 (2005): 677-681.
- ^ Hann, Christine L., et al. "Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer." Cancer research 68.7 (2008): 2321-2328.
- ^ http://www.asianscientist.com/tech-pharma/abt-199-bh-3-mimetic-wehi-phase-ia-trial-chronic-lymphocytic-leukemia/
- ^ http://www.stokesentinel.co.uk/Miracle-drug-cured-cancer-Amazing-recovery/story-21080535-detail/story.html
- ^ http://www.genengnews.com/gen-news-highlights/cephalon-to-spend-225m-to-purchase-gemin-x-for-phase-ii-sclc-candidate/81244855/
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- ^ Hsu SY, Lin P, Hsueh AJ (Sep 1998). "BOD (Bcl-2-related ovarian death gene) is an ovarian BH3 domain-containing proapoptotic Bcl-2 protein capable of dimerization with diverse antiapoptotic Bcl-2 members". Mol. Endocrinol. 12 (9): 1432–40. doi:10.1210/mend.12.9.0166. PMID 9731710.
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- ^ Gil-Parrado S, Fernández-Montalván A, Assfalg-Machleidt I, Popp O, Bestvater F, Holloschi A, Knoch TA, Auerswald EA, Welsh K, Reed JC, Fritz H, Fuentes-Prior P, Spiess E, Salvesen GS, Machleidt W (Jul 2002). "Ionomycin-activated calpain triggers apoptosis. A probable role for Bcl-2 family members". J. Biol. Chem. 277 (30): 27217–26. doi:10.1074/jbc.M202945200. PMID 12000759.
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- ^ Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES (Apr 2002). "Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria". J. Biol. Chem. 277 (16): 13430–7. doi:10.1074/jbc.M108029200. PMID 11832478.
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- ^ Tagami S, Eguchi Y, Kinoshita M, Takeda M, Tsujimoto Y (Nov 2000). "A novel protein, RTN-XS, interacts with both Bcl-XL and Bcl-2 on endoplasmic reticulum and reduces their anti-apoptotic activity". Oncogene 19 (50): 5736–46. doi:10.1038/sj.onc.1203948. PMID 11126360.
- ^ Iwahashi H, Eguchi Y, Yasuhara N, Hanafusa T, Matsuzawa Y, Tsujimoto Y (Nov 1997). "Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy". Nature 390 (6658): 413–7. doi:10.1038/37144. PMID 9389483.
- ^ Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D, Brown RH (Jul 2004). "Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria". Neuron 43 (1): 19–30. doi:10.1016/j.neuron.2004.06.021. PMID 15233914.
- ^ Naumovski L, Cleary ML (Jul 1996). "The p53-binding protein 53BP2 also interacts with Bc12 and impedes cell cycle progression at G2/M". Mol. Cell. Biol. 16 (7): 3884–92. PMC 231385. PMID 8668206.
External links
- The Bcl-2 Family Database
- The Bcl-2 Family at celldeath.de
- Bcl-2 publications sorted by impact at caspases.org
- bcl-2 Genes at the US National Library of Medicine Medical Subject Headings (MeSH)
- c-bcl-2 Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)
Neoplasm: Tumor suppressor genes/proteins and Oncogenes/Proto-oncogenes
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Ligand |
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Receptor |
Wnt signaling pathway
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Hedgehog signaling pathway
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TGF beta signaling pathway
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Receptor tyrosine kinase
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- ONCO: ErbB/c-ErbB
- c-Met
- c-Ret
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JAK-STAT signaling pathway
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Intracellular signaling P+Ps |
Wnt signaling pathway
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- ONCO: Beta-catenin
- TSP: APC
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TGF beta signaling pathway
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Akt/PKB signaling pathway
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Hippo signaling pathway
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TSP: Neurofibromin 2/Merlin
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MAPK/ERK pathway
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- TSP: Neurofibromin 1
- ONCO: c-Ras
- HRAS
- c-Raf
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Other/unknown
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Nucleus |
Cell cycle
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- TSP: p53
- pRb
- WT1
- p16/p14arf
- ONCO: CDK4
- Cyclin D
- Cyclin E
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DNA repair/Fanconi
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Ubiquitin ligase
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Transcription factor
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- TSP: KLF6
- ONCO: AP-1
- c-Myc
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Mitochondria |
- Apoptosis inhibitor: SDHB
- SDHD
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Other/ungrouped |
- c-Bcl-2 - Notch - Stathmin
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Apoptosis signaling pathway
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Fas path |
Ligand
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Receptor
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Intracellular
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- Death-inducing signaling complex
- Cytochrome c
- Caspase 9
- Caspase 3
- Pro-apoptotic:
- BAX
- BAK1/Bcl-2 homologous antagonist killer
- Bcl-2-associated death promoter
- Anti-apoptotic:
- Bcl-2
- Bcl-xL
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TNF path |
Ligand
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Receptor
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- Tumor necrosis factor receptor
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Intracellular
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- FADD
- Caspase 8
- Caspase 3
- BID
- TRAF2
- ASK-1
- MEKK1
- IKK
- IκBα
- MKK7
- JNK
- NF-κB
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Other |
Intracellular
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- IAPs
- XIAP
- NAIP
- Survivin
- c-IAP-1
- c-IAP-2
- Apoptosis-inducing factor
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B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)
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