BAD (BCL2-antagonist of cell death)
2004-08-01 Jean-Loup Huret , Sylvie Senon AffiliationGenetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
DNA/RNA
Description
The gene spans 14,9 kb, on reverse strand
Transcription
alternate splicing encoding for the same protein
Proteins
Description
168 amino acids, 18,4 kDa.; BH3 only Bcl2 family member (do not possess BH1, 2 and 4 domains). The BH3 domain is essential for proapoptotic function. There is structural similarities between the Bcl2 family proteins and bacterial toxins which form membrane pores after oligomerisation. Do not possess a transmembrane domain in COOH term, in contrast with a number of other BCL2 family members; may be phosphorylated on serine residues (see below).
Expression
wide
Localisation
cytoplasm vs membrane of the mitochondria (see below)
Function
Proapoptotic protein:
In its inactive form, Bad is phosphorylated. Proteins which phosphorylate BAD are: RAF1, ribosomal S6 kinase 1 (p90/RSK1), AKT/PKB (PI3K-AKT pathway) at Serine 136 (in murine BAD), PKA at Ser 155, PIM1and PIM2 at Ser 112 (Ser 75, 99, and 118 in human BAD correspond to Ser 112, 136, and 155 in murine BAD respectively). Phosphorylated BAD interacts with 14-3-3 scaffold proteins in the cytoplasm (14-3-3 is a protein which can interact with a hundred other proteins).
Cleavage of the 14-3-3 protein by caspase-3 allows the release of BAD from its association with the 14-3-3 protein and facilitates BAD translocation from the cytosol to the mitochondria. Under apoptotic stimuli also, calcineurin (Ca++ activated protein phosphatase) dephosphorylates BAD, also allowing its dissociation from 14-3-3.
Once BAD is dephosphorylated (posttranslational modification), it is active; it translocates to the outer membrane of the mitochondria (like other proapototic members of the Bcl2 family), and forms heterodimers with BCL-XL (and, to a lesser extend, heterodimers with BCL2 or BCL2L2) to block BCL-XL antiapoptotic function. Dimers BCL-XL /BAD are similar to dimers BCL-XL /BAK
Homology
Bcl2 family members:
The antiapoptotic members with BH 1 to 4 domains: BCL2 (18q21), BCL1L1/BCLX-L (20q11), BCL2L2/BCL-W (14q11), BCL1L10/BCL-B/BOO/DIVA (15q21), BCL2A1/BFL1/A1 (15q24), BNIP1/EIB-19K (5q33), MCL1 (1q21)
The proapoptotic members with BH 1 to 3 domains: BAK1/BCL2L7 (6p21), BAX (19q13), BCL2L13/BCL-Rambo/MIL1 (22q11), BOK/MTD/BCL2L9 (2q37)
The only-BH3 apoptotic members: BBC3/PUMA (19q13), BCL2L11/BIM/BOD (2q13), BID (22q11), BIK/NBK/BBC1 (22q13), BLK (8p23), BMF (15q14), BNIP3/NIP3 (10q26), BMIP3L/NIX (8p21), HRK/DP5/BID3 (12q24), PMAIP1/NOXA (18q21)
Implicated in
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 12965220 | 2003 | Mutation of BAD within the BH3 domain impairs its phosphorylation-mediated regulation. | Adachi M et al |
| 14996500 | 2004 | Control of proliferation by Bcl-2 family members. | Bonnefoy-Berard N et al |
| 12239175 | 2002 | Role of PI3-kinase-dependent Bad phosphorylation and altered transcription in cytokine-mediated neutrophil survival. | Cowburn AS et al |
| 10949026 | 2000 | 14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation. | Datta SR et al |
| 9372935 | 1997 | Bad is a BH3 domain-containing protein that forms an inactivating dimer with Bcl-XL. | Kelekar A et al |
| 11878929 | 2002 | Induction of Bad-mediated apoptosis by Sindbis virus infection: involvement of pro-survival members of the Bcl-2 family. | Moriishi K et al |
| 9388232 | 1997 | Dimerization properties of human BAD. Identification of a BH-3 domain and analysis of its binding to mutant BCL-2 and BCL-XL proteins. | Ottilie S et al |
| 14996493 | 2004 | Structural biology of the Bcl-2 family of proteins. | Petros AM et al |
| 14996494 | 2004 | Bcl-2 family members: integrators of survival and death signals in physiology and pathology [corrected]. | Schinzel A et al |
| 14996501 | 2004 | Bcl-2 family members and disease. | Sorenson CM et al |
| 10195903 | 1999 | Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. | Wang HG et al |
| 12657644 | 2003 | Cleavage of 14-3-3 protein by caspase-3 facilitates bad interaction with Bcl-x(L) during apoptosis. | Won J et al |
| 12954615 | 2003 | The PIM-2 kinase phosphorylates BAD on serine 112 and reverses BAD-induced cell death. | Yan B et al |
| 7834748 | 1995 | Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. | Yang E et al |
| 9381178 | 1997 | Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. | del Peso L et al |
Other Information
Locus ID:
NCBI: 572
MIM: 603167
HGNC: 936
Ensembl: ENSG00000002330
Variants:
dbSNP: 572
ClinVar: 572
TCGA: ENSG00000002330
COSMIC: BAD
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
PharmGKB
| Entity ID | Name | Type | Evidence | Association | PK | PD | PMIDs |
|---|---|---|---|---|---|---|---|
| PA24684 | AKT1 | Gene | Pathway | associated |
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 36883564 | 2023 | mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer. | 6 |
| 37014579 | 2023 | AMPK/mTOR/p70S6K axis prevents apoptosis of Porphyromonas gingivalis-infected gingival epithelial cells via Bad(Ser136) phosphorylation. | 2 |
| 36883564 | 2023 | mTOR inhibition overcomes RSK3-mediated resistance to BET inhibitors in small cell lung cancer. | 6 |
| 37014579 | 2023 | AMPK/mTOR/p70S6K axis prevents apoptosis of Porphyromonas gingivalis-infected gingival epithelial cells via Bad(Ser136) phosphorylation. | 2 |
| 32710568 | 2021 | Hypertonicity counteracts MCL-1 and renders BCL-XL a synthetic lethal target in head and neck cancer. | 4 |
| 33651899 | 2021 | Vanillic acid mitigates the impairments in glucose metabolism in HepG2 cells through BAD-GK interaction during hyperinsulinemia. | 2 |
| 34011960 | 2021 | BAD regulates mammary gland morphogenesis by 4E-BP1-mediated control of localized translation in mouse and human models. | 4 |
| 34633547 | 2021 | Difference in the binding mechanisms of ABT-263/43b with Bcl-xL/Bcl-2: computational perspective on the accurate binding free energy analysis. | 0 |
| 32710568 | 2021 | Hypertonicity counteracts MCL-1 and renders BCL-XL a synthetic lethal target in head and neck cancer. | 4 |
| 33651899 | 2021 | Vanillic acid mitigates the impairments in glucose metabolism in HepG2 cells through BAD-GK interaction during hyperinsulinemia. | 2 |
| 34011960 | 2021 | BAD regulates mammary gland morphogenesis by 4E-BP1-mediated control of localized translation in mouse and human models. | 4 |
| 34633547 | 2021 | Difference in the binding mechanisms of ABT-263/43b with Bcl-xL/Bcl-2: computational perspective on the accurate binding free energy analysis. | 0 |
| 31906916 | 2020 | Evaluation of apoptosis and angiogenesis in ectopic and eutopic stromal cells of patients with endometriosis compared to non-endometriotic controls. | 22 |
| 32223928 | 2020 | EGFR-independent EGFR-mutant lung adenocarcinoma cells depend on Bcl-xL and MCL1 for survival. | 0 |
| 32473226 | 2020 | The anti-apoptotic proteins Bcl-2 and Bcl-xL suppress Beclin 1/Atg6-mediated lethal autophagy in polyploid cells. | 8 |
Citation
Jean-Loup Huret ; Sylvie Senon
BAD (BCL2-antagonist of cell death)
Atlas Genet Cytogenet Oncol Haematol. 2004-08-01
Online version: http://atlasgeneticsoncology.org/gene/130/bad
