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BNIP3 (Bcl-2/adenovirus E1B 19kD-interacting protein 3)

Written2007-10Sang-Gi Paik, Hayyoung Lee
Department of Biology, School of Biosciences, Biotechnology, Chungnam National University, Daejeon 305-764, Korea.

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)NIP3
HGNC (Hugo) BNIP3
HGNC Alias symbNip3
HGNC Alias namenineteen kD interacting protein-3
HGNC Previous nameBCL2/adenovirus E1B 19kDa interacting protein 3
LocusID (NCBI) 664
Atlas_Id 822
Location 10q26.3  [Link to chromosome band 10q26]
Location_base_pair Starts at 131967683 and ends at 131982013 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping BNIP3.png]
Fusion genes
(updated 2017)		Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
BNIP3 (10q26.3) / MARCH6 (5p15.2)

DNA/RNA

 
Description 14.23 kb on reverse strand; 6 exons
Transcription mRNA in MCF-7 cells are 1.7kb (major) and 1.5 kb (minor) and 1.3 kb (minor).

Protein

 
  Domain map of BNIP3 protein; BH3 domain (Bcl-2 holomogy 3 domain); TM domain (transmembrane domain)
Description 194 amino acids; 1 BH3 domain and 1 TM domain; BH3 only Bcl2 family member. The TM domain and C-terminal tail are essential for mitochondrial membrane localization and proapoptotic function. The predicted molecular weight is 21.5 kDa. BNIP3 migrates as 30 kDa monomeric form and 60 kDa dimeric form on SDS-PAGE.
Expression BNIP3 is detected in mouse oviduct, uterus, spleen, lung, stomach, brain, seminal, lacrimal, submaxillary, heart, kidney, liver. It can be detected in cell lines such as HeLa, 293T, RAW264.7 and K562 cells. Its expression can be induced in both normal and cancer tissues that experience hypoxia or hypoxia-like conditions. Other stimuli, such as nitric oxide or arsenic trioxide, are also reported to induce BNIP3 expression.
Localisation Outer mitochondrial membrane
Function Proapoptotic protein;
BNIP3 leads to opening of the mitochondrial permeability transition pore (PTP) thereby abolishing the proton electrochemical gradient and this is followed by chromatin condensation and DNA fragmentation. BNIP3 leads necrosis-like apoptosis. Unusually to the other Bcl-2 family proteins, the BNIP3-induced cell death depends not on BH3 domain but on C-terminal TM domain. BNIP3-induced cell death is known to be independent the nuclear translocation of AIF. However, whether caspase activation and cytochrome c release are involved in the cell death remains controversial. BNIP3 can induce autophagy. However whether the consequence of the autophagy is the cell death or survival remains to be established.
Since BNIP3 is induced by hypoxia through transcription factor HIF-1, it was postulated to play a role in hypoxia-induced cell death. Hypoxia-induced acidosis augments the proapoptotic function of BNIP3.
Homology The close homologue: BNIP3L/ BNIP3a/ Nix/ B5 (8q21)
The BH3-only Bcl2 family members: BBC3/PUMA (19q13), BCL2L11/BIM/BOD (2Q13), BID (22q11), BIK/NBK/BBC1 (22q13), BLK (8q23), BMF (15Q14), HRK/DP5/BID3 (12q24), PMAIP1/NOXA (18q21)

Implicated in

Note
  
Entity Pancreatic cancer
Prognosis Pancreatic adenocarcinoma is highly resistant to chemical and radiation therapy, and has an extremely poor prognosis. Reduced expression of BNIP3 increased resistance to gemcitabine and 5-fluoro-uracil (5-FU) and showed a good correlation with reduced patient survival.
Oncogenesis In most cases of pancreatic adenocarcinoma, BNIP3 expression was not detected even in response to hypoxia. The promoter of BNIP3 is located within a CpG island and is methylated in most pancreatic cancer cell lines. Restoration of BNIP3 expression by the methyltransferase inhibitor, 5-aza-deoxycytidine, induced death of pancreatic cancer cells in response to hypoxia.
  
  
Entity Colorectal cancer
Oncogenesis Methylation of BNIP3 in 66% of primary colorectal cancer
  

Bibliography

Upregulation of BNIP3 by 5-aza-2'-deoxycytidine sensitizes pancreatic cancer cells to hypoxia-mediated cell death.
Abe T, Toyota M, Suzuki H, Murai M, Akino K, Ueno M, Nojima M, Yawata A, Miyakawa H, Suga T, Ito H, Endo T, Tokino T, Hinoda Y, Imai K
Journal of gastroenterology. 2005 ; 40 (5) : 504-510.
PMID 15942716
 
Intrinsic chemoresistance to gemcitabine is associated with decreased expression of BNIP3 in pancreatic cancer.
Akada M, Crnogorac-Jurcevic T, Lattimore S, Mahon P, Lopes R, Sunamura M, Matsuno S, Lemoine NR
Clinical cancer research : an official journal of the American Association for Cancer Research. 2005 ; 11 (8) : 3094-3101.
PMID 15837765
 
Activation of Ras up-regulates pro-apoptotic BNIP3 in nitric oxide-induced cell death.
An HJ, Maeng O, Kang KH, Lee JO, Kim YS, Paik SG, Lee H
The Journal of biological chemistry. 2006 ; 281 (45) : 33939-33948.
PMID 16954213
 
Selective silencing of the hypoxia-inducible factor 1 target gene BNIP3 by histone deacetylation and methylation in colorectal cancer.
Bacon AL, Fox S, Turley H, Harris AL
Oncogene. 2007 ; 26 (1) : 132-141.
PMID 16799636
 
Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins.
Boyd JM, Malstrom S, Subramanian T, Venkatesh LK, Schaeper U, Elangovan B, D'Sa-Eipper C, Chinnadurai G
Cell. 1994 ; 79 (2) : 341-351.
PMID 7954800
 
Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia.
Bruick RK
Proceedings of the National Academy of Sciences of the United States of America. 2000 ; 97 (16) : 9082-9087.
PMID 10922063
 
The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis.
Chen G, Ray R, Dubik D, Shi L, Cizeau J, Bleackley RC, Saxena S, Gietz RD, Greenberg AH
The Journal of experimental medicine. 1997 ; 186 (12) : 1975-1983.
PMID 9396766
 
Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis.
Erkan M, Kleeff J, Esposito I, Giese T, Ketterer K, Büchler MW, Giese NA, Friess H
Oncogene. 2005 ; 24 (27) : 4421-4432.
PMID 15856026
 
The carboxy terminal C-tail of BNip3 is crucial in induction of mitochondrial permeability transition in isolated mitochondria.
Kim JY, Cho JJ, Ha J, Park JH
Archives of biochemistry and biophysics. 2002 ; 398 (2) : 147-152.
PMID 11831844
 
Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3.
Kubasiak LA, Hernandez OM, Bishopric NH, Webster KA
Proceedings of the National Academy of Sciences of the United States of America. 2002 ; 99 (20) : 12825-12830.
PMID 12226479
 
Regulation of BNIP3 in normal and cancer cells.
Lee H, Paik SG
Molecules and cells. 2006 ; 21 (1) : 1-6.
PMID 16511341
 
Aberrant methylation and silencing of the BNIP3 gene in colorectal and gastric cancer.
Murai M, Toyota M, Suzuki H, Satoh A, Sasaki Y, Akino K, Ueno M, Takahashi F, Kusano M, Mita H, Yanagihara K, Endo T, Hinoda Y, Tokino T, Imai K
Clinical cancer research : an official journal of the American Association for Cancer Research. 2005 ; 11 (3) : 1021-1027.
PMID 15709167
 
Silencing of the hypoxia-inducible cell death protein BNIP3 in pancreatic cancer.
Okami J, Simeone DM, Logsdon CD
Cancer research. 2004 ; 64 (15) : 5338-5346.
PMID 15289340
 
BNIP3 heterodimerizes with Bcl-2/Bcl-X(L) and induces cell death independent of a Bcl-2 homology 3 (BH3) domain at both mitochondrial and nonmitochondrial sites.
Ray R, Chen G, Vande Velde C, Cizeau J, Park JH, Reed JC, Gietz RD, Greenberg AH
The Journal of biological chemistry. 2000 ; 275 (2) : 1439-1448.
PMID 10625696
 
BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore.
Vande Velde C, Cizeau J, Dubik D, Alimonti J, Brown T, Israels S, Hakem R, Greenberg AH
Molecular and cellular biology. 2000 ; 20 (15) : 5454-5468.
PMID 10891486
 
BNip3 and signal-specific programmed death in the heart.
Webster KA, Graham RM, Bishopric NH
Journal of molecular and cellular cardiology. 2005 ; 38 (1) : 35-45.
PMID 15623420
 
Adenovirus E1B-19K/BCL-2 interacting protein BNIP3 contains a BH3 domain and a mitochondrial targeting sequence.
Yasuda M, Theodorakis P, Subramanian T, Chinnadurai G
The Journal of biological chemistry. 1998 ; 273 (20) : 12415-12421.
PMID 9575197
 
Nitric oxide induces BNIP3 expression that causes cell death in macrophages.
Yook YH, Kang KH, Maeng O, Kim TR, Lee JO, Kang KI, Kim YS, Paik SG, Lee H
Biochemical and biophysical research communications. 2004 ; 321 (2) : 298-305.
PMID 15358175
 

Citation

This paper should be referenced as such :
Paik, SG ; Lee, H
BNIP3 (Bcl-2/adenovirus E1B 19kD-interacting protein 3)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(3):195-196.
Free journal version : [ pdf ]   [ DOI ]

External links

Nomenclature
HGNC (Hugo)BNIP3   1084
Cards
AtlasBNIP3ID822ch10q26
Entrez_Gene (NCBI)BNIP3    BCL2 interacting protein 3
AliasesNIP3
GeneCards (Weizmann)BNIP3
Ensembl hg19 (Hinxton)ENSG00000176171 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000176171 [Gene_View]  ENSG00000176171 [Sequence]  chr10:131967683-131982013 [Contig_View]  BNIP3 [Vega]
ICGC DataPortalENSG00000176171
TCGA cBioPortalBNIP3
AceView (NCBI)BNIP3
Genatlas (Paris)BNIP3
SOURCE (Princeton)BNIP3
Genetics Home Reference (NIH)BNIP3
Genomic and cartography
GoldenPath hg38 (UCSC)BNIP3  -     chr10:131967683-131982013 -  10q26.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)BNIP3  -     10q26.3   [Description]    (hg19-Feb_2009)
GoldenPathBNIP3 - 10q26.3 [CytoView hg19]  BNIP3 - 10q26.3 [CytoView hg38]
ImmunoBaseENSG00000176171
genome Data Viewer NCBIBNIP3 [Mapview hg19]  
OMIM603293   
Gene and transcription
Genbank (Entrez)AF002697 AK130264 AK222626 AK295136 BC009342
RefSeq transcript (Entrez)NM_004052
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)BNIP3
Alternative Splicing GalleryENSG00000176171
Gene ExpressionBNIP3 [ NCBI-GEO ]   BNIP3 [ EBI - ARRAY_EXPRESS ]   BNIP3 [ SEEK ]   BNIP3 [ MEM ]
Gene Expression Viewer (FireBrowse)BNIP3 [ Firebrowse - Broad ]
GenevisibleExpression of BNIP3 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)664
GTEX Portal (Tissue expression)BNIP3
Human Protein AtlasENSG00000176171-BNIP3 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ12983   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ12983  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ12983
Splice isoforms : SwissVarQ12983
PhosPhoSitePlusQ12983
Domains : Interpro (EBI)BNIP3   
Domain families : Pfam (Sanger)BNIP3 (PF06553)   
Domain families : Pfam (NCBI)pfam06553   
Conserved Domain (NCBI)BNIP3
Blocks (Seattle)BNIP3
PDB (RSDB)2J5D    2KA1    2KA2   
PDB Europe2J5D    2KA1    2KA2   
PDB (PDBSum)2J5D    2KA1    2KA2   
PDB (IMB)2J5D    2KA1    2KA2   
Structural Biology KnowledgeBase2J5D    2KA1    2KA2   
SCOP (Structural Classification of Proteins)2J5D    2KA1    2KA2   
CATH (Classification of proteins structures)2J5D    2KA1    2KA2   
SuperfamilyQ12983
Human Protein Atlas [tissue]ENSG00000176171-BNIP3 [tissue]
Peptide AtlasQ12983
HPRD04482
IPIIPI00290409   IPI01009553   
Protein Interaction databases
DIP (DOE-UCLA)Q12983
IntAct (EBI)Q12983
BioGRIDBNIP3
STRING (EMBL)BNIP3
ZODIACBNIP3
Ontologies - Pathways
QuickGOQ12983
Ontology : AmiGOautophagy of mitochondrion  response to hypoxia  protein binding  nucleus  nucleus  nuclear envelope  nuclear envelope  nucleoplasm  cytoplasm  mitochondrion  mitochondrion  mitochondrial outer membrane  mitochondrial outer membrane  endoplasmic reticulum  endoplasmic reticulum  apoptotic process  cell death  granzyme-mediated apoptotic signaling pathway  response to bacterium  positive regulation of autophagy  negative regulation of mitochondrial fusion  cardiac muscle cell apoptotic process  positive regulation of cardiac muscle cell apoptotic process  negative regulation of mitochondrial membrane potential  positive regulation of necrotic cell death  postsynaptic density  viral process  positive regulation of macroautophagy  cerebral cortex development  dendrite  integral component of mitochondrial outer membrane  mitochondrial membrane  mitochondrial membrane  mitochondrial protein catabolic process  identical protein binding  protein homodimerization activity  positive regulation of apoptotic process  negative regulation of apoptotic process  regulation of programmed cell death  positive regulation of programmed cell death  positive regulation of programmed cell death  positive regulation of protein complex disassembly  mitochondrial fragmentation involved in apoptotic process  negative regulation of membrane potential  regulation of mitochondrial membrane permeability  autophagic cell death  response to axon injury  oligodendrocyte differentiation  brown fat cell differentiation  GTPase binding  neuron apoptotic process  positive regulation of mitochondrial calcium ion concentration  defense response to virus  response to hyperoxia  negative regulation of cell death  cellular response to hydrogen peroxide  cellular response to mechanical stimulus  cellular response to cobalt ion  cellular response to hypoxia  cellular response to hypoxia  reactive oxygen species metabolic process  positive regulation of mitochondrial fission  positive regulation of release of cytochrome c from mitochondria  response to oxygen-glucose deprivation  mitochondrial outer membrane permeabilization  mitochondrial outer membrane permeabilization  toxin transport  negative regulation of mitochondrial membrane permeability involved in apoptotic process  positive regulation of autophagy of mitochondrion  regulation of aerobic respiration  intrinsic apoptotic signaling pathway in response to hypoxia  negative regulation of reactive oxygen species metabolic process  
Ontology : EGO-EBIautophagy of mitochondrion  response to hypoxia  protein binding  nucleus  nucleus  nuclear envelope  nuclear envelope  nucleoplasm  cytoplasm  mitochondrion  mitochondrion  mitochondrial outer membrane  mitochondrial outer membrane  endoplasmic reticulum  endoplasmic reticulum  apoptotic process  cell death  granzyme-mediated apoptotic signaling pathway  response to bacterium  positive regulation of autophagy  negative regulation of mitochondrial fusion  cardiac muscle cell apoptotic process  positive regulation of cardiac muscle cell apoptotic process  negative regulation of mitochondrial membrane potential  positive regulation of necrotic cell death  postsynaptic density  viral process  positive regulation of macroautophagy  cerebral cortex development  dendrite  integral component of mitochondrial outer membrane  mitochondrial membrane  mitochondrial membrane  mitochondrial protein catabolic process  identical protein binding  protein homodimerization activity  positive regulation of apoptotic process  negative regulation of apoptotic process  regulation of programmed cell death  positive regulation of programmed cell death  positive regulation of programmed cell death  positive regulation of protein complex disassembly  mitochondrial fragmentation involved in apoptotic process  negative regulation of membrane potential  regulation of mitochondrial membrane permeability  autophagic cell death  response to axon injury  oligodendrocyte differentiation  brown fat cell differentiation  GTPase binding  neuron apoptotic process  positive regulation of mitochondrial calcium ion concentration  defense response to virus  response to hyperoxia  negative regulation of cell death  cellular response to hydrogen peroxide  cellular response to mechanical stimulus  cellular response to cobalt ion  cellular response to hypoxia  cellular response to hypoxia  reactive oxygen species metabolic process  positive regulation of mitochondrial fission  positive regulation of release of cytochrome c from mitochondria  response to oxygen-glucose deprivation  mitochondrial outer membrane permeabilization  mitochondrial outer membrane permeabilization  toxin transport  negative regulation of mitochondrial membrane permeability involved in apoptotic process  positive regulation of autophagy of mitochondrion  regulation of aerobic respiration  intrinsic apoptotic signaling pathway in response to hypoxia  negative regulation of reactive oxygen species metabolic process  
Pathways : KEGGFoxO signaling pathway    Legionellosis   
NDEx NetworkBNIP3
Atlas of Cancer Signalling NetworkBNIP3
Wikipedia pathwaysBNIP3
Orthology - Evolution
OrthoDB664
GeneTree (enSembl)ENSG00000176171
Phylogenetic Trees/Animal Genes : TreeFamBNIP3
HOGENOMQ12983
Homologs : HomoloGeneBNIP3
Homology/Alignments : Family Browser (UCSC)BNIP3
Gene fusions - Rearrangements
Fusion : Fusion_HubBNIP3--MARCH6    BNIP3--PPP2R2D    CPSF3L--BNIP3    GAK--BNIP3   
Fusion : QuiverBNIP3
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerBNIP3 [hg38]
dbVarBNIP3
ClinVarBNIP3
MonarchBNIP3
1000_GenomesBNIP3 
Exome Variant ServerBNIP3
GNOMAD BrowserENSG00000176171
Varsome BrowserBNIP3
Genomic Variants (DGV)BNIP3 [DGVbeta]
DECIPHERBNIP3 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisBNIP3 
Mutations
ICGC Data PortalBNIP3 
TCGA Data PortalBNIP3 
Broad Tumor PortalBNIP3
OASIS PortalBNIP3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICBNIP3  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DBNIP3
Mutations and Diseases : HGMDBNIP3
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch BNIP3
DgiDB (Drug Gene Interaction Database)BNIP3
DoCM (Curated mutations)BNIP3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)BNIP3 (select a term)
intoGenBNIP3
NCG6 (London) select BNIP3
Cancer3DBNIP3(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM603293   
Orphanet
DisGeNETBNIP3
MedgenBNIP3
Genetic Testing Registry BNIP3
NextProtQ12983 [Medical]
GENETestsBNIP3
Target ValidationBNIP3
Huge Navigator BNIP3 [HugePedia]
ClinGenBNIP3
Clinical trials, drugs, therapy
MyCancerGenomeBNIP3
Protein Interactions : CTD
Pharm GKB GenePA25394
PharosQ12983
Clinical trialBNIP3
Miscellaneous
canSAR (ICR)BNIP3 (select the gene name)
HarmonizomeBNIP3
DataMed IndexBNIP3
Probes
Litterature
PubMed169 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXBNIP3
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Jan 1 18:47:37 CET 2021
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