Identifiers
B-cell CLL/lymphoma 2
HUGO:BCL2, HGNC:990, ENTREZ:596, UNIPROT:P10415, GENECARDS:GC18M060763
HUGO:BCL2 HGNC:990 ENTREZ:596 UNIPROT:P10415

Maps_Modules
HMC:ACTIVATING_INVASION_AND_METASTASIS
 EMT Senescence   / EMT_REGULATORS 
 EMT Senescence   / MITOCHONDRIA_OXIDATIVE_STRESS 
HMC:RESISTING_CELL_DEATH
 Regulated Cell Death   / APOPTOSIS 
 Regulated Cell Death   / STARVATION_AUTOPHAGY 
 Regulated Cell Death   / CASPASES 
 Regulated Cell Death   / DEATH_RECEPTOR_PATHWAYS 
 Regulated Cell Death   / MOMP_REGULATION 
 Regulated Cell Death   / NECROPTOSIS 
 Regulated Cell Death   / RCD_GENES 
 Regulated Cell Death   / ER_STRESS 
HMC:EVADING_GROWTH_SUPPRESSORS
 Survival   / MAPK 

References
PMID:22039431
The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates.
The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family.
Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death.
The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function.
Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis
PMID:23064052
BCL2 and BCL2L1 are known to be overexpressed in several cancers.
PMID:11704864
Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer.
PMID:23850759
PMID:23430059
PMID:23377657
PMID:17446862
BCL2 protein can target Raf-1 (C-Raf) to mitochondria.
PMID:8929532

References
em_re1547( EMT Senescence  ):
PMID:11704864
Transcriptional regulation of bcl-2 by nuclear factor kappa B
em_emtc_emtc_re430( EMT Senescence  ):
PMID:22039431
The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates.
The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family.
Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death.
The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function.
Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis
PMID:9872359
A oncogene-derived protein, Bcl2, confers negative control in the pathway of cellular suicide machinery.
A Bcl2-homologous protein, Bax, promotes cell death by competing with Bcl2.
While Bax???Bax homodimers act as apoptosis inducers, Bcl2??? Bax heterodimer formation evokes a survival signal for the cells.
Both Bcl2 and Bax are transcriptional targets for the tumour suppressor protein, p53, which induces cell cycle arrest or apoptosis in response to DNA damage.
em_emtc_emtc_re431( EMT Senescence  ):
Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic protines) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic protines)work against programmed cell death.
em_emtc_emtc_re433( EMT Senescence  ):
PMID:12667443
p53 induces apoptosis by target gene regulation and transcription-independent signaling.
A fraction of induced p53 translocates to the mitochondria of apoptosing tumor cells. Targeting p53 to mitochondria is sufficient to launch apoptosis.
Evidence that p53 translocation to the mitochondria occurs in vivo in irradiatedthymocytes was shown.
em_emtc_emtc_re436( EMT Senescence  ):
PMID:11463392
BBC3 (so-called PUMA, p53 upregulated modulator of apoptosis) as a target for activation by p53.
This gene encodes two BH3 domain???containing proteins that are induced in cells following p53 activation.
BBC3 binds to BCL2, localize to the mitochondria to induce cytochrome c release, and activate the rapid induction of programmed cell death.
Antisense inhibition of PUMA expression reduced the apoptotic response to p53, and PUMA is likely to play a role inmediating p53-induced cell death through the cytochrome c/Apaf-1???dependent pathway.
PMID:11463391
PUMA was found to be exclusively mitochondrial and to bind to BCL2 and BCL2L1 through a BH3 domain.
It is via this binding to BBC3 (an apoptic inducer) that BCL2 and BCL2L1 exhibit their anti-apoptic effect.

Maps_Modules
HMC:RESISTING_CELL_DEATH
 Regulated Cell Death   / APOPTOSIS 
 Regulated Cell Death   / STARVATION_AUTOPHAGY 
 Regulated Cell Death   / CASPASES 
 Regulated Cell Death   / DEATH_RECEPTOR_PATHWAYS 
 Regulated Cell Death   / MOMP_REGULATION 
 Regulated Cell Death   / NECROPTOSIS 
 Regulated Cell Death   / RCD_GENES 

References
rc_re1409( Regulated Cell Death  ):
PMID:9115213
S70 phosphorylation of BCL2 necessary for its antiapoptotic function
in NSF/N1.H7 mouse leukemia cells BCL2 mutants transfection) in response to IL-3, etoposide, or bryostatin-1, a PKC activator
PMID:9738012
suggest that PRKCA is the main PRKC BCL2 kinase in HL60 human acute myeloid leukemia cell line
PMID:10677502
ERK1/2 is a BCL2 S70 kinase in NSF/N1.H7 cells stimulated with IL-3
in vitro direct phosphorylation
PMID:11323415
JNK is a BCL2 S70 kinase in NSF/N1.H7 cells upon IL-3 withdrawal
rc_re102:( Regulated Cell Death  ) PMID:14747474
rc_re582( Regulated Cell Death  ):
PMID:9430630
PMID:15486085
BCL2-BimEL interaction in mitochondrial fraction independent of BIM S69 phosphorylation status
PMID:15724238
in human tonsil B cells, constitutive interaction
PMID:10198631
rc_re597:( Regulated Cell Death  ) testtest
rc_re602( Regulated Cell Death  ):
PMID:11546872
in HEK293T, coIP
Y2H
rc_re607:( Regulated Cell Death  ) PMID:9130713
rc_re1116( Regulated Cell Death  ):
PMID:19834492
in different cancer cell lines (CEM, C666-1 and HCT116) that express empty or BCL2 plasmids
rc_re1408:( Regulated Cell Death  ) reactionType:is.a
rc_re1868( Regulated Cell Death  ):
PMID:17244528
Bcl-2 located in Endoplasmic reticulum lower intrareticulum Calcium and thus inhibate Calcium flux

Maps_Modules
HMC:RESISTING_CELL_DEATH
 Regulated Cell Death   / APOPTOSIS 
 Regulated Cell Death   / STARVATION_AUTOPHAGY 
 Regulated Cell Death   / CASPASES 
 Regulated Cell Death   / DEATH_RECEPTOR_PATHWAYS 
 Regulated Cell Death   / MOMP_REGULATION 
 Regulated Cell Death   / NECROPTOSIS 
 Regulated Cell Death   / RCD_GENES 

Maps_Modules
HMC:RESISTING_CELL_DEATH
 Regulated Cell Death   / APOPTOSIS 
 Regulated Cell Death   / STARVATION_AUTOPHAGY 
 Regulated Cell Death   / CASPASES 
 Regulated Cell Death   / DEATH_RECEPTOR_PATHWAYS 
 Regulated Cell Death   / MOMP_REGULATION 
 Regulated Cell Death   / NECROPTOSIS 
 Regulated Cell Death   / RCD_GENES 

References
rc_re1420( Regulated Cell Death  ):
PMID:8929532
in vitro RAF1:BCL2 interaction
in 293, overexpression of BCL2 induces relocalization of RAF1-GFP to mitochondria
in vitro phosphorylation of BAD by RAF1
in 293T, over-expression of a mitochondria-targeted version of RAF1 induces phosphorylation of BAD (controls: plasma membrane targeted RAF1, kinase dead mutant)
BCL2 over-expression targets RAF1 kinase domain-GFP to mitochondria
mitochondria-targeted RAF1 (deleted for Ras binding domain) potentiates BCL2 anti-apoptotic activity in 32D.3 exposed to staurosporine or upon IL-3 withdrawal
rc_re1407:( Regulated Cell Death  ) reactionType:is.a
rc_re1409( Regulated Cell Death  ):
PMID:9115213
S70 phosphorylation of BCL2 necessary for its antiapoptotic function
in NSF/N1.H7 mouse leukemia cells BCL2 mutants transfection) in response to IL-3, etoposide, or bryostatin-1, a PKC activator
PMID:9738012
suggest that PRKCA is the main PRKC BCL2 kinase in HL60 human acute myeloid leukemia cell line
PMID:10677502
ERK1/2 is a BCL2 S70 kinase in NSF/N1.H7 cells stimulated with IL-3
in vitro direct phosphorylation
PMID:11323415
JNK is a BCL2 S70 kinase in NSF/N1.H7 cells upon IL-3 withdrawal

Maps_Modules
HMC:RESISTING_CELL_DEATH
 Regulated Cell Death   / APOPTOSIS 
 Regulated Cell Death   / STARVATION_AUTOPHAGY 
 Regulated Cell Death   / CASPASES 
 Regulated Cell Death   / DEATH_RECEPTOR_PATHWAYS 
 Regulated Cell Death   / MOMP_REGULATION 
 Regulated Cell Death   / NECROPTOSIS 
 Regulated Cell Death   / RCD_GENES 

References
rc_re1407:( Regulated Cell Death  ) reactionType:is.a
rc_re1000( Regulated Cell Death  ):
influenceDelete: reactants to re
hierarchical:post-MOMP
reactionType:casp.cleavage
PMID:10409669
CASP3 mediated cleavage of BCL2 in vitro and in HL60 cells or MCF7 with reconstituted CASP3 expression after exposure to staurosporine
no cleavage by CASP7
PMID:20139069
FKBP8 protects BCL2 from CASP3-mediated degradation
rc_re1001( Regulated Cell Death  ):
PMID:19706769
in HEK293, co-precipitation of ectopically expressed tagged proteins
in HeLa cells infected with G0S2-HA Ad virus, co-precipitation of endogenous BCL2 with HA antibody
in HCT116 (transient transfection), interaction detected by FRET
Competition between G0S2 and BAX for binding to BCL2
in HEK293, co-IP experiments with tagged protein shows that G0S2 competes with BAX for binding to BCL2
rc_re1002:( Regulated Cell Death  ) PMID:9660918
rc_re1406( Regulated Cell Death  ):
PMID:18845789
unphosphorylated TP53 from coIP experiments with okadaic acid (PKC inhibitor) or ceramide C2 (potent inductor of PP1/2A
PMID:26801188
rc_re1410( Regulated Cell Death  ):
PMID:14980220
in vitro with in vitro translated proteins
in H460 cells (endogenously expressed proteins), upon 3-Cl-AHPC
effect of Bcl2 phosphorylation on binding to NUR77 unknown, even if loop region of Bcl2 between BH3 and BH4, which contains the phosphorylation sites, domain was mapped as the interaction domain

Maps_Modules
HMC:RESISTING_CELL_DEATH
 Regulated Cell Death   / APOPTOSIS 
 Regulated Cell Death   / STARVATION_AUTOPHAGY 
 Regulated Cell Death   / CASPASES 
 Regulated Cell Death   / DEATH_RECEPTOR_PATHWAYS 
 Regulated Cell Death   / MOMP_REGULATION 
 Regulated Cell Death   / NECROPTOSIS 
 Regulated Cell Death   / RCD_GENES 

References
rc_re1469:( Regulated Cell Death  ) PMID:20865015

Maps_Modules
HMC:RESISTING_CELL_DEATH
 Regulated Cell Death   / APOPTOSIS 
 Regulated Cell Death   / STARVATION_AUTOPHAGY 
 Regulated Cell Death   / CASPASES 
 Regulated Cell Death   / DEATH_RECEPTOR_PATHWAYS 
 Regulated Cell Death   / MOMP_REGULATION 
 Regulated Cell Death   / NECROPTOSIS 
 Regulated Cell Death   / RCD_GENES 

References
rc_re1832( Regulated Cell Death  ):
PMID:23377657
PMID:11323415
PMID:19037093
Phosphorylation of Bcl-2 by JNK1 substantially reduce the affinity of BCL2 for Beclin1 leading to activation of autophagy

Maps_Modules
HMC:RESISTING_CELL_DEATH
 Regulated Cell Death   / APOPTOSIS 
 Regulated Cell Death   / STARVATION_AUTOPHAGY 
 Regulated Cell Death   / CASPASES 
 Regulated Cell Death   / DEATH_RECEPTOR_PATHWAYS 
 Regulated Cell Death   / MOMP_REGULATION 
 Regulated Cell Death   / NECROPTOSIS 
 Regulated Cell Death   / RCD_GENES 

1. BCL2@Cytosol
2. BCL2|​pho@Cytosol
3. BCL2|​ubi@Cytosol

1. BCL2@Endopasmic Reticulum
2. BCL2|​pho@Endopasmic Reticulum

1. BCL2@Mitochondria

1. BCL2@Mitochondrial inner membrane
2. BCL2|​pho@Mitochondrial inner membrane
3. BCL2|​unk@Mitochondrial inner membrane

1. AMBRA1:​BCL2@Cytosol
2. BAX|​S163_unk|​T167_unk:​BCL2@Cytosol
3. BCL2:​BECN1:​UVRAG@Cytosol

1. BAX:​BCL2@Endopasmic Reticulum
2. BAK1:​BCL2@Endopasmic Reticulum
3. BCL2:​TMBIM6@Endopasmic Reticulum

1. BAX:​BCL2@Mitochondria
2. BAK1:​BCL2@Mitochondria
3. BBC3:​BCL2@Mitochondria
4. BCL2:​p53*@Mitochondria

1. BCL2:​HRK@Mitochondrial inner membrane
2. BBC3:​BCL2@Mitochondrial inner membrane
3. BCL2:​G0S2@Mitochondrial inner membrane
4. BCL2:​p53*@Mitochondrial inner membrane
5. BCL2:​TMBIM6@Mitochondrial inner membrane
6. BCL2:​BCL2L11@Mitochondrial inner membrane
7. BCL2:​BMF|​unk@Mitochondrial inner membrane
8. BCL2|​unk:​NR4A1@Mitochondrial inner membrane
9. BAD|​S91_unk:​BCL2@Mitochondrial inner membrane
10. BCL2:​cleaved_BID*|​myr@Mitochondrial inner membrane
11. BAX|​S163_unk|​T167_unk:​BCL2@Mitochondrial inner membrane

1. BAD_binding partners*@Mitochondria → BCL2@Mitochondria
2. BAX@Cytosol + BCL2@Mitochondria → BAX:​BCL2@Mitochondria
3. BCL2@Mitochondria + BAK1@Mitochondria → BAK1:​BCL2@Mitochondria
4. p53*@Mitochondria + BCL2@Mitochondria → BCL2:​p53*@Mitochondria
5. BBC3@Mitochondria + BCL2@Mitochondria → BBC3:​BCL2@Mitochondria
6. rBCL2@Nucleus → BCL2@Mitochondria
7. BCL2|​unk@Mitochondrial inner membrane → cleaved~BCL2*@Mitochondrial inner membrane
8. BCL2|​unk@Mitochondrial inner membrane + G0S2@Cytosol → BCL2:​G0S2@Mitochondrial inner membrane
9. TMBIM6@Mitochondrial inner membrane + BCL2|​unk@Mitochondrial inner membrane → BCL2:​TMBIM6@Mitochondrial inner membrane
10. rBCL2@Nucleus → BCL2@Cytosol
11. BCL2@Cytosol → BCL2|​unk@Mitochondrial inner membrane
12. BCL2@Cytosol → BCL2@Cytosol
13. BCL2|​unk@Mitochondrial inner membrane + p53*|​S15_unk@Cytosol → BCL2:​p53*@Mitochondrial inner membrane
14. BCL2@Mitochondrial inner membrane → BCL2|​unk@Mitochondrial inner membrane
15. BCL2|​pho@Mitochondrial inner membrane → BCL2|​unk@Mitochondrial inner membrane
16. BCL2@Mitochondrial inner membrane → BCL2|​pho@Mitochondrial inner membrane
17. BCL2|​unk@Mitochondrial inner membrane + NR4A1@Cytosol → BCL2|​unk:​NR4A1@Mitochondrial inner membrane
18. BAD|​S91_unk:​BCL2@Mitochondrial inner membrane → BCL2@Mitochondrial inner membrane + BAD|​pho@Cytosol
19. BCL2@Cytosol → BCL2|​ubi@Cytosol
20. BCL2|​ubi@Cytosol → degraded
21. BCL2:​BECN1:​UVRAG@Cytosol → BCL2@Cytosol + BECN1@Cytosol + UVRAG@Cytosol
22. BCL2@Cytosol + BAX|​S163_unk|​T167_unk@Cytosol → BAX|​S163_unk|​T167_unk:​BCL2@Cytosol
23. BAX|​S163_unk|​T167_unk:​BCL2@Cytosol → Apoptotic death@Cytosol
24. BCL2@Cytosol → BCL2|​pho@Cytosol
25. AMBRA1@Cytosol + BCL2@Cytosol → AMBRA1:​BCL2@Cytosol
26. BCL2|​pho@Mitochondrial inner membrane → Ca2+ Wave@Cytosol
27. rBCL2@Nucleus → BCL2@Cytosol
28. TMBIM6@Endopasmic Reticulum + BCL2@Endopasmic Reticulum → BCL2:​TMBIM6@Endopasmic Reticulum
29. BCL2:​TMBIM6@Endopasmic Reticulum → Ca2+ homeostasis@Endopasmic Reticulum
30. BCL2@Endopasmic Reticulum → BCL2|​pho@Endopasmic Reticulum
31. BCL2@Endopasmic Reticulum + BAX@Endopasmic Reticulum → BAX:​BCL2@Endopasmic Reticulum
32. BCL2@Endopasmic Reticulum + BAK1@Endopasmic Reticulum → BAK1:​BCL2@Endopasmic Reticulum
33. BECN1@Cytosol + BCL2@Cytosol + UVRAG@Cytosol → BCL2:​BECN1:​UVRAG@Cytosol
34. BCL2L11@Mitochondrial inner membrane + BCL2|​pho@Mitochondrial inner membrane → BCL2:​BCL2L11@Mitochondrial inner membrane
35. cleaved_BID*|​myr@Mitochondrial inner membrane + BCL2|​pho@Mitochondrial inner membrane → BCL2:​cleaved_BID*|​myr@Mitochondrial inner membrane
36. BBC3@Mitochondrial inner membrane + BCL2|​pho@Mitochondrial inner membrane → BBC3:​BCL2@Mitochondrial inner membrane
37. BAD|​S91_unk|​active@Mitochondrial inner membrane + BCL2|​pho@Mitochondrial inner membrane → BAD|​S91_unk:​BCL2@Mitochondrial inner membrane
38. BMF|​unk@Mitochondrial inner membrane + BCL2|​pho@Mitochondrial inner membrane → BCL2:​BMF|​unk@Mitochondrial inner membrane
39. HRK@Mitochondrial inner membrane + BCL2|​pho@Mitochondrial inner membrane → BCL2:​HRK@Mitochondrial inner membrane
40. BCL2|​pho@Mitochondrial inner membrane + BAX|​S163_unk|​T167_unk@Mitochondrial inner membrane → BAX|​S163_unk|​T167_unk:​BCL2@Mitochondrial inner membrane
41. gBCL2@Nucleus → BCL2@Mitochondria
42. su_mpk1_mpk1_s953 → BCL2@Mitochondria + BAD@Mitochondria

1. cleaved~Caspase9*@Mitochondrial intermembrane space → cleaved~Caspase9*@Cytosol
2. COX5A@Cytosol → COX5A@Mitochondrial inner membrane
3. IRE1-alpha*:​Unfolded protein*@Endopasmic Reticulum + TRAF2@Cytosol → MCL1|​pho|​hm2:​TRAF2:​Unfolded protein*@Endopasmic Reticulum
4. ITPR*@Endopasmic Reticulum → low Ca2+ level@Endopasmic Reticulum
5. GRB2:​RAF1|​pho:​RAS*|​pho:​RTK*:​SOS*@Plasma Membrane → GRB2:​RAS*|​pho:​RTK*:​SOS*@Plasma Membrane + RAF1|​pho@Mitochondria