Index Caspase CARD/DED/BIR Bcl-2  DD TNF/TNFR Kinases ILs Viral Lipid Engulf TF RING Toll Other Apop Other NFkB Alphabet

Bcl-2 Family
 
gene proposed name
products 
(proteins)
species function binding partners other features 3D Motif Structure KO tramscriptional regulators regulation signals locus
bcl-2,(5') 
BCL2 Bcl-2alpha human, mouse, rat, LThamster, P.p., P.m., bovine, deer, cat, chicken inhibit /induce Bcl-2, Bax ,  Bcl-xL, Bcl-xS, Hrk, Bad, Bak, BAG-1, c-raf, R-ras, c-ras, calcineurin Abeta, Bid, Nip1, Nip2, Nip3, Bim, beclin, BI-1, Rad9, Btf, Bis, Noxa, Bmf, Pin1, FKBP38, HAX1, HSpin, ITM2B(s), Nur77, PP1a, calcineurin, Cdc2 oncogene of folicular lymphoma, Ub 1 BH4/P?/BH3/BH1/BH2/TM L Aiolos, B-Myb, c-Myb, v-Myb, Brn-3a/(-), AP1, CREB, p53, E2F1, c-Myc, Rb, AP2, Bcl-6, NF-kB, NF-AT, PAX8, RAR, RXR, GR, WT1, PU.1, Pi1, STATs, SRF, GATA-1, GLI1, SP1/ER(1, 2), FLI-1, E2F1, Mitf, HOX11
IL1b, IL2, IL3, IL4, IL5(N), IL6, IL7, IL8, IL10, IL15, IL18, IL21, IL24, AH, G-CSF(-), GM-CSF, EGF, VEGF, IFNb, PEDF, bFGF, TNF, Fas, OX40, BAFF, TACI, CD3/CD28, PMA, BCR, IGFBP2, SST, substance P, PTHrP, TRH, CD31, CD69, CD90, LTD4, LPS, Hp, Sd, Mt, Ang, bombesin, neurotrophins, prolactin, FLT3L, SHH, irrrad, ischemic stress adaptation, progesterone, O stress, antioxidant, GSH, UVB, NO, 3-NP, OA, PTDS, DTDS, curcumin, As2O3, melarsoprol, gluc.redct., PTK, PP2A, TGFa, TGFb(N), COX2, DEX, estrogen, RA, D3, MEQ, IGF-I, Am80, T3, IKKb, PI3K, Akt, PTEN, Src, JNK(?), avb5, E-Cad., p38, MKP1, Par4, Bit1, AES, TLE1, hemopoietins, Ask1, Cdk1, Cdk6, v-cyclin, CDC2, AUF1, Nef, JAK2, JAK3, NGF, PLCg2, PKCd, GH, Plakoglobin, minocycline, tat, finasteride, caffeine
18q21.3

Bcl-2beta
human, mouse,chicken




BH4/BH3/BH1/BH2



bcl-x (human, mouse)



BCL2L1 Bcl-xL human, mouse, rat, pig, chicken, sheep, bovine, rabbit, dog, zebrafish(bclx, blp1) inhibit Bax, Bcl-xS, Bcl-xL, Hrk, Bik, Bid, Bad, Bak, Bcl-xL, Bcl-2, Bim, Apaf-1 , BI-1, Btf, Aven, Aiolos, Bpr, Diva/Bcl-B, Bcl-G, Bmf, FKBP38, HSpin, Noxa, p53, Rad9, SphK2, Siva1, chelerythrine highly expressed in erythroid
human (N,X), rat, xL/Bak BH4/P?/BH3/BH1/BH2/TM L GATA-1,GATA-4, Ets2, PU.1, NF-kB, CREB, Bcl-6, STAT3(-), STAT5A&B, STAT6, Brn-3a, EWS, PAX3, Pax5, Smad1, p53, Bcl6, AFX, TEL, c-Myc, Csx TCR/CD3/28/PMA, CTLA4/B7, BCR, EGF, PEDF, GM-CSF(-), M-CSF, TGFa/(-), TGFb, Bmp2, Epo, thrombopoietin, IL1, IL3, IL4, IL6, IL8, IL10, IL10/12, IL15, IL18, IL21, TNFa, OX40, BAFF, TACI, 4-1BB/4-1BBL, HGF, SCF, DEX, MUC1, COX2, estrogen, progesterone, CD40, CD31, hypoxia, H2O2, NO, LPS, Ec, Hp, Ma, Sm, g-irrad., UVA, DEX, GADD153, ECM, EGFR, Taxol, p38, Akt/PI3K, PKCb, estramustine, 3-NP, MPTP, Jnk, c-Abl, DDR1, HTLVs, tax, HCV core, HBx, ALK, NIK, MKK4, ERKs, finasteride, TCDD 20q11.2

Bcl-xS
human,mouse,rat
promote
Bcl-2, Bcl-xL, Bcl-xS


BH4/BH3/TM

NF-kB
NGF(-), IL18, finasteride


Bcl-x beta
human, mouse, rat, chicken
inhibit/promote


BH4/BH3/BH1/BH2





Bcl-x DTM
mouse




BH4/BH3/BH1/BH2





Bcl-x gamma
mouse
inhibit



BH4/BH3/BH1/BH2
1



bax (human, mouse)




BAX




Bax alpha human, mouse, rat, bovine, sheep, cat, dog, deer, frog, zebrafish promote/inhibit Bax, Bcl-2, Bcl-xL, Bid, Bcl-B, E1B 19K, Bif-1, Ku70, 14-3-3sigma, 14-3-3q, NS5A, Asc function similar to Bak, Ub, cleaved by calpain, highest levels in hematopoietic cells
1 BH4/BH3/BH1/BH2/TM L p53(no res.), p73, p63AIRE, Brn-3a, Gfi-1, myc(-), PLZF, Sp1, Ahr, HMGs, RARb,NF-kB, Brn3a IL1b, IL6(-), IL8, IL10, IL24, TNFa, BAFF, TACI, TCR, PMA, LPS, b-glucan, Hp, Ma, Mt, Sd, ischemia, NO, MEQ, G-CSF, SCF, SST, TRH, prolactin, ATP, SSI-1, DEX, TGFb, COX2, JAK3,PKR, FRAP, LATS1, PAHs, Expi, H2O2, ROS, MG132, DHA, lactacystin, g-irrad, hypoxiaYAP, TCDD, cisplatin, KA, calpain 19q13.3-4
omega
rat inhibit Bax-alpha, Bcl-2

BH4/BH3/BH1/BH2



sigma
human
induce
Bcl-xL,Mtd,Bax,Bak,Bfl1

BH4/BH3/BH1/(BH2)/TM



beta, gamma, delta,epsilon, psi, zeta human





p53

epsilon(2)

induce
Bcl-2, Bcl-xL, Baxalpha

BH4/BH3




kappa
rat, mouse




BH3/BH1/BH2/TM




bak/bak2/bak3(mouse) BAK1 Bak human, mouse, rat, pig, sheep promote/inhibit Bcl-xL, Bcl-2Mcl1, E1B 19K, E6AP function similar to Bax, Ub, highest levels in epithelium, preB
xL/Bak BH4/BH3/BH1/BH2/TM L p53, E2F1, RARb, NF-kB estrogen, progesterone, IFNg, IL1a, RANTES, PMA, LPS, EV71, g-irrad., Raf, IL6(-), DEX, UV, camptothecin, butyric acid  6p21.3-.2


N-Bak
mouse
promote/inhibit







mcl-1
MCL1 Mcl-1 human, mouse, rat, sheep, pig, dog, chicken, zebrafish (a, b), carp inhitit Bax, Bad, Bmf, Mtd, DAD1,fortilin, tankyrase 1 highest level in myeloid,  lymphocytes, APCs, Macrophage-inducible gene, casp3

BH4/BH3/BH1/BH2/TM L SRF, AP1, Elk-1, E2F1, E1A, PU.1, Stat3, CREB, c-Myc IL3, IL6, IL7, TNFa, IFNg, GM-CSF, SCF, PDGF, Subst.P, HGFVEGF, Thrombin, LMP1, E1A, PI3K, DNA damage, UVBPMA, LPSCSBG, Ct, Lm, Ma, Mt, Ng, Ye, HHV8, UV, Epo, gonadotropins, estrogen, myocardial infarction, cAMP, Aktp38, Jak, PI3K, IEX1S, Jnk, Nef, flavopiridol, DIM, ER, AdV, TCDD 1q21

Mcl-1sDTM,Mcl-1s
human
induce



BH4/BH3




bfl-1/A1 BCL2A1 A1/Bfl-1/GRS human(a,b,c),mouse(a,b,c,d), rat, chicken inhibit Bax, Mtd, ING1 highest level in myeloid, preB, APCs, lymphocytes

BH4/BH3/BH1/BH2/TM L NF-kB, AP1, STATs, C/EBPa, C/EBPb, HMG-IC GM-CSF, G-CSF, LPS, b-glucanLd, Lm, Ma, Mt, Ng, Tg, HHV8, CD40, CD31, TNFa, IL1b/TNFa, IFNa, TCR/CD3, 4-1BB, PMA, BCR, TGFb, PLCg2, D3, DEX, IL10, irrad, Am80, T3, butyric acid, DIM 15q24.3
bcl-w BCL2L2 Bcl-w human, mouse, rat inhibit Bim, Bmf, PP1aa important for spermatogenesis (1, 2), highest level in brain
L BH4/BH3/BH1/BH2/TM L
ischemia, HGFR, Subst.P, TCDD 14q11.2-q12
mtd*
BOK
Bok-L/MTD
human, rat, mouse, chicken
promote
Mcl-1, Bfl-1
highest level in bone marrow (but not in ovary/testis)

BH4/BH3/BH1/BH2/TM
E2F1, p53
FSH, SCF, serum, TCDD



Bok-S
rat
promote



BH4/BH31/BH2/TM



diva BCL2L10 Diva/Boo, Bcl-b/Nrh mouse, rat, human promote/(-)/inhibit Apaf-1, vBcl-2, Bcl-xL, Bcl-xS, Bcl-2, Bik, Bak, Diva, Bax ovary/testis-specific in mouse adults
BH4/BH3/BH1/BH2/TM 1

15q21
bcl-g

BCLG
Bcl-GL
human (S, M, L),mouse, rat
promote
Bcl-xL, Bcl-2
testis-specific

?/BH3/(BH1)/BH2



12p12
Bcl-Gs
human, mouse
promote
Bcl-xL

BH2




MIL1
BCL2L13
Bcl-Rambo/MIL1
human, mouse, rat
induce



BH4/BH3/BH1/BH2/Ex/TM


22q11
bpr
BCL2L12
BPR
human, mouse, rat

 Bcl-xL
highest level in preB, bone marrow, lymphocytes

BH2

c-Myc

19q13.3
BPR variant 1
human




   

bfk
LOC148280
Bfk
human, mouse, rat
promote



BH4/BH3/BH1/BH2


1p13.1
NR-13

NR13
quail, chick, zebrafish
inhibit

 
BH4/BH3/BH1/BH2/TM
NF-kB
v-src

xRII

xRII
X.laevis
inhibit



BH4/BH3/BH1/BH2/TM



xR1

xRI
X.laevis




BH4/BH3/BH1/BH2/TM



Ced-9

Ced-9
C.elegans, briggsae,
inhibit
Ced-4(1,2,3,4,5), Egl-1

1w/Ced9 BH4/BH3/BH1/BH2/TM 1

3
drob1

Drob1/DEBCL/BOK/BG1/Dborg1
fly, Ag
promote



BH4/BH3/BH1/BH2/TM

UV
42E-43A
buffy

Buffy
fly, Ag
 inhibit



BH4/BH3/BH1/BH2/TM


2 48A-E
bhp1

BHP1
sponges(G.c., S.d.)
inhibit



BH4?/3?/BH1/BH2/TM



harakiri HRK Hrk/DP5, Bid3
human, mouse/rat promote Bcl-xL, Bcl-2, E1B 19K, p32 BH3-only subfamily, RGCs, 4-cell embryo
BH3/TM 1
DREAM, E2F1 NGF, b-amyloid, IL3, Fas, T3, progesterone, methylation, KA , JNK, calcineurin, TCDD, KCl
12p13.1.
bik/nbk/blk BIK Bik/Nbk/Blk human(bik)/mouse(blk), rat promote Bcl-xL, Bcl-2a, E1B 19K, BHRF1 BH3-only subfamily

P/BH3/TM 1 p53 TGFb, BCR, CD27TNFa, CD40, SCF, Nef, E1A, RA, Estrogen, LPS, hypoxia-ischemia, TCDD 22q13.2-13.3
nip1
BNIP1
NIP1/BNIP1
human (a, b,c ), mouse, rat, Dm, Ag, At,

Bcl-2, E1B 19K, Bcl-xL, alpha-SNAP
 Sec20, no BH3

BH3?//TM

AP1
5q33-q34
nip3 BNIP3 NIP3/BNIP3 human, mouse, zebrafish, C.e. promote Bcl-2, E1B 19K, Nip3, CD47, Ced-9, Ced-3 BH3-only subfamily?
BH3?/TM 1 HIF1a, IRF4, Egr1, PLAGL2, AIRE TRAIL, PMA, hypoxia, dsRNA, MHV, UV, T3, NO, cGMP, ErbB2 14q11.2-q12
bnip3l
BNIP3L
BNIP3L/Nix/BNIP3alpha
human, zebrafish, mouse
promote
Bcl-2, E1B19K
 BH3 subfamily(?)

BH3?/TM
1
FKHRL1
Fas, myocardial, hypertrophy, Nc, hypoxia, camptothecin
8p21


sNix
mouse
protect








bnip3h

BNIP3h
human
promote








bid(human, mouse) BID Bid human, mouse, rat, chicken promote Bcl-xL, Bcl-2, Bax, tBid, monolysocardiolipin cleaved by casp-8, -3, -2, cathepsins, calpain, granzyme B; Ub; myristoylated 1, 2 Bcl-xL-like with BH3, highest level in APCs, NK & their precursors
L p53, PLZF, AP1, E2F1 IL1b, TNFa, Fas, LPS, Subst.P, hypoxia, camptothecin, lactacystin; Hsp90, MG132, TCDD 22q11.2
bad BAD Bad, Bad S human, mouse, rat, zebrafish promote Bcl-xL, Bcl-2, Bcl-w(-), glucokinase, Mcl1, Ced-9, BHRF1(-), 14-3-3 BH3-only subfamily, casp substrate xL/Bad P/BH3
L E2F1, HIF1 IL2, IL3, Estrogen, SDF1, Subst.P, TRH, GLP2, LPS, Ca, Mt, RSKs, PKBalpha, TIP30, FTIs, Akt/PI3K, PKA, PAK1, Pak5, PKCtheta, p70S6K, MEKs, ERKs, Jnk, CKII, GSK3, , Cdc2, calcineurin, PP1a, PP2a, p75NTR, Nef, Ub, US3, finasteride, camptothecin, butyric acidnicotine, hypoxia 11q13
bim BCL2L11 Bim/Bod human(S,L,EL, AD, gamma), mouse(S,L,EL), rat (S,M,L), pig(partial) promote Bcl-2, Bcl-xL, Bcl-w, VDAC, dynein, humanin
BH3-only subfamily, caspase substrate w/Dlc8 dynein-BD/BH3/TM L FKHR-L1, E2F1 GR, RARa, p53, Smad3 IL2, ,IL3, GM-CSF, TCR, TGFb, LPS, Lm, NGF, IGF-I, MIP3, detachment, b1, EGFR, ERKs, JNK, PKC, PKA, calcineurin, IL10, CD40, UV, estrogen, DEX, KA, Ub, cAMP, FK506, CsA, KCl
2p23.3-p13.1
bmf
BMF
Bmf
human, mouse, rat
promote
Bcl-2, Bcl-xL, Mcl1, Bcl-w, DLC2
BH3-only subfamily

DLC/BH3


Jnk, anoikis, UV
15q14
puma/bbc3
BBC3
Puma/Bbc3
human (a, b, g, d), mouse, rat
promote
Bcl-2, Bcl-xL
BH3-only subfamily

L
p53, p73, c-Myc, E2F1, B-Myb, AP1, CREB, NF-kB
IFNa, IFNg, DEX, serum, IGF1, IGFBP2, EGF, flagellin, g-irrad, UV, ER stress, VSV, p300
19q13.3-q13.4
apr
PMAIP1
Noxa/Apr/TN3
human, mouse, rat, pig
promote
Bcl-xL, Bcl-2
BH3-only subfamily
(BH3/)BH3, highest in B, NK, APCs
L
p53, p73, E2F1, IRF3
IFNsTNFa, IL2, IL15, irrad, UV, MeDNA, flagellin, PMA, RA, heat shock, HBx, E1A, estrogencantharidin, Blimp1
18q21.31
egl-1
Egl-1 C. elegans promote Ced-9 BH3-only subfamily w/Ced9
BH3 1 ces-1, ces2, tra-1
5
cip-1

CIP-1
C.elegans
 
Ced-9
 
BH3




BHRF1

BHRF1
EBV, HVP, CHV15, HVp
inhibit
Bik, Bok, Rab acceptor 1, HAX1


BH4/BH3/BH1/BH2/TM



LMH-5W
LMH-5W/A179L
ASFV(E-70, BA71V, LIL 20/1)
inhibit



(BH4?)/BH3/BH1/BH2/TM



A9
A9
AHV1
inhibit



BH4/BH3/BH1/BH2/TM



Gene 16
ORF16
SHV(2,11), MMRV, AHV3
inhibit


BH4/BH3/BH1/BH2/TM



v-bcl-2
vBcl-2
KSAHV, HVP
inhibit
Diva, Aven, Bak
1 BH4/BH3/BH1/BH2/TM





M11
MHV68
inhibit
Aven


BH4/BH3/BH1/BH2/TM







BHV4
inhibit



BH4/BH3/BH1/BH2/TM






FPV039
FPV




BH4/BH3/BH1/BH2/TM






ORF81
LDV1
 


BH4/BH3/BH1/BH2/TM




BALF1

BALF1
BALF1(EBV), E4(EHV2, AHV1), ORF1(CHV), PHV
inhibit
Bax,Bak


BH4/BH3/BH1/BH2/TM




E1B

E1B 19K
hAdV(2,5,7,40,41), bAdV(2,3), mAdV(1), cAdV(1) etc
inhibit
NIP1-3, Nbk, Hrk, Bax, Btf, Ced4, Casp8

BH4?/BH3/BH1/BH2




Incorrectly reported
BRCC2, BRAG-1, BmP109, p193, APE1820, ITM2B(s), MAP-1, Rad9, Spike, SphK2, SP1610



belongs to other families

no homo. to BHs




Domains of Bcl-2 Family (Under construction)
 
 


Borner, Minn, Zhang
BH4 a1 Huang, Hirotani, Hirotani, Shimizu, Denis
non-cons
Vance, Chang, Cheng, Clem, Fujita, Fang, Srivastava, Wang, Kirsch , Rodi,
BH3 a2 Boyd, Chittenden, Han., Zha,Simonian(1, 2), Diaz, Ink, Ottilie(1, 2), Simonen, Kelekar, Elangovan, Cosulich, Holinger, Nechushtan, Polster, Moreau
BH1-BH2
Yin,Cheng, Revilla, D'Sa-Eipper, Holmgreen, Kawatani,
TM
Nguyen,Priault, Tremblais, Nechushtan,

On-line References

Review of

General  by Korsmeyer et al. (Genes Dev 1999), Adams & Cory (Science 1998), Chao & Korsmeyer (Annu. Rev. Immunol. 1998)
AKT on apoptosis by  Franke et al. (Cell 1997)
Cytochrome c release in Cell Death Differ (direct access to Issue Dec. 2000)
Immune system by Marsden & Strasser (Annu Rev Immunol)
Mictochonria & apoptosis by Green & Reed (Science 1998)
Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells by Wang (PNAS 2000)



Structures of Bcl-2 family members (Inohara 2001).  Bid is a protein which have the folding similar to Bcl-xL and Bax, and used to be believed to have homology to BH3 motif only.  Zebrafish BNIP3 does not contain a BH3 consensus motif (BNIP1 also does not conserve a  BH3 domain).  Bax and Bak have a BH4 region which plays important roles on their molecular functions. However, several researchers call it "BH4-like" but not BH4, although their definition of BH4 is unclear.   See the upper table for the references.

Images

Rotating Bcl-xL (Aritomi et al., 1997)



Copyright by Naohiro Inohara, Department of Pathology, University of of Michigan Medical School
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