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

Identity

Other namesNIP3
HGNC (Hugo) BNIP3
LocusID (NCBI) 664
Location 10q26.3
Location_base_pair Starts at 133781204 and ends at 133795435 bp from pter ( according to hg19-Feb_2009)  [Mapping]

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

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
  

External links

Nomenclature
HGNC (Hugo)BNIP3   1084
Entrez_Gene (NCBI)BNIP3  664  BCL2/adenovirus E1B 19kDa interacting protein 3
Cards
AtlasBNIP3ID822ch10q26
GeneCards (Weizmann)BNIP3
Ensembl (Hinxton)ENSG00000176171 [Gene_View]  chr10:133781204-133795435 [Contig_View]  BNIP3 [Vega]
AceView (NCBI)BNIP3
Genatlas (Paris)BNIP3
euGene (Indiana)664
SOURCE (Stanford)NM_004052
Genomic and cartography
GoldenPath (UCSC)BNIP3  -  10q26.3   chr10:133781204-133795435 -  10q26.3   [Description]    (hg19-Feb_2009)
EnsemblBNIP3 - 10q26.3 [CytoView]
Mapping of homologs : NCBIBNIP3 [Mapview]
OMIM603293   
Gene and transcription
Genbank (Entrez)AF002697 AK222626 AK295136 BC009342 BC021989
RefSeq transcript (SRS)NM_004052
RefSeq transcript (Entrez)NM_004052
RefSeq genomic (SRS)AC_000142 NC_000010 NT_008818 NW_001838014
RefSeq genomic (Entrez)AC_000142 NC_000010 NT_008818 NW_001838014
Consensus coding sequences : CCDS (NCBI)BNIP3
Cluster EST : UnigeneHs.144873 [ SRS ] Hs.144873 [ NCBI ]
Alternative Splicing : Fast-db (Paris)17100
Alternative Splicing GalleryENSG00000176171
Gene ExpressionBNIP3 [ NCBI-GEO ]   BNIP3 [ EBI - ARRAY_EXPRESS ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ12983 (SRS) Q12983 (Uniprot)
With graphics : InterProQ12983
Splice isoforms : SwissVarQ12983(Swissvar)
Domains : Interpro (SRS)BNIP3   
Domains : Interpro (EBI)BNIP3   
Related proteins : CluSTrQ12983
Domain families : Pfam (SRS)BNIP3 (PF06553)   
Domain families : Pfam (Sanger)BNIP3 (PF06553)   
Domain families : Pfam (NCBI)pfam06553   
Blocks (Seattle)Q12983
PDB (SRS)2J5D    2KA1    2KA2   
PDB (PDBSum)2J5D    2KA1    2KA2   
PDB (IMB)2J5D    2KA1    2KA2   
PDB (RSDB)2J5D    2KA1    2KA2   
Human Protein AtlasENSG00000176171
HPRD04482
IPIIPI00290409   IPI01009553   
Protein Interaction databases
DIP (DOE-UCLA)Q12983
IntAct (EBI)Q12983
FunCoupENSG00000176171
REACTOMEBNIP3
BioGRIDBNIP3
InParanoidQ12983
Interologous Interaction database Q12983
Polymorphism : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)BNIP3
SNP (GeneSNP Utah)BNIP3
SNP : HGBaseBNIP3
Genetic variants : HAPMAPBNIP3
Somatic Mutations in Cancer : COSMICBNIP3 
CONAN: Copy Number AnalysisBNIP3 
Mutations and Diseases : HGMDBNIP3
OMIM603293   
GENETests603293   
Disease Genetic AssociationBNIP3
Huge Navigator BNIP3 [HugePedia]  BNIP3 [HugeCancerGEM]
Genomic VariantsBNIP3
snp3D : Map Gene to Disease664
General knowledge
Homologs : HomoloGeneBNIP3
Homology/Alignments : Family Browser (UCSC)BNIP3
Phylogenetic Trees/Animal Genes : TreeFamBNIP3
Chemical/Protein Interactions : CTD664
Chemical/Pharm GKB GenePA25394
Clinical trialBNIP3
Cancer Resource (Charite)ENSG00000176171
Ontology : AmiGOresponse to hypoxia  protein binding  nucleus  nucleus  nuclear envelope  nucleoplasm  cytoplasm  mitochondrion  mitochondrion  DNA fragmentation involved in apoptotic nuclear change  chromatin remodeling  apoptotic process  apoptotic process  anti-apoptosis  induction of apoptosis  cell death  cell death  induction of apoptosis by intracellular signals  negative regulation of survival gene product expression  negative regulation of mitochondrial fusion  membrane  integral to membrane  dendrite  integral to mitochondrial outer membrane  mitochondrial membrane  mitochondrial membrane  identical protein binding  protein homodimerization activity  positive regulation of protein complex disassembly  mitochondrial fragmentation involved in apoptosis  interspecies interaction between organisms  negative regulation of membrane potential  regulation of mitochondrial membrane permeability  protein heterodimerization activity  autophagic cell death  brown fat cell differentiation  GTPase binding  neuron apoptosis  defense response to virus  response to hyperoxia  cellular response to hydrogen peroxide  cellular response to mechanical stimulus  cellular response to cobalt ion  cellular response to hypoxia  reactive oxygen species metabolic process  positive regulation of mitochondrial fission  positive regulation of release of cytochrome c from mitochondria  
Ontology : EGO-EBIresponse to hypoxia  protein binding  nucleus  nucleus  nuclear envelope  nucleoplasm  cytoplasm  mitochondrion  mitochondrion  DNA fragmentation involved in apoptotic nuclear change  chromatin remodeling  apoptotic process  apoptotic process  anti-apoptosis  induction of apoptosis  cell death  cell death  induction of apoptosis by intracellular signals  negative regulation of survival gene product expression  negative regulation of mitochondrial fusion  membrane  integral to membrane  dendrite  integral to mitochondrial outer membrane  mitochondrial membrane  mitochondrial membrane  identical protein binding  protein homodimerization activity  positive regulation of protein complex disassembly  mitochondrial fragmentation involved in apoptosis  interspecies interaction between organisms  negative regulation of membrane potential  regulation of mitochondrial membrane permeability  protein heterodimerization activity  autophagic cell death  brown fat cell differentiation  GTPase binding  neuron apoptosis  defense response to virus  response to hyperoxia  cellular response to hydrogen peroxide  cellular response to mechanical stimulus  cellular response to cobalt ion  cellular response to hypoxia  reactive oxygen species metabolic process  positive regulation of mitochondrial fission  positive regulation of release of cytochrome c from mitochondria  
Other databases
Probes
Probes : ImagenesBNIP3 Related clones (RZPD - Berlin)
Litterature
PubMed88 Pubmed reference(s) in Entrez
PubGeneBNIP3
iHOPBNIP3

Bibliography

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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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, Bˆºchler MW, Giese NA, Friess H
Oncogene. 2005 ; 24 (27) : 4421-4432.
PMID 15856026
 
Aberrant DNA methylation associated with silencing BNIP3 gene expression in haematopoietic tumours.
Murai M, Toyota M, Satoh A, Suzuki H, Akino K, Mita H, Sasaki Y, Ishida T, Shen L, Garcia-Manero G, Issa JP, Hinoda Y, Tokino T, Imai K
British journal of cancer. 2005 ; 92 (6) : 1165-1172.
PMID 15756280
 
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
 
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
 
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
 
Regulation of BNIP3 in normal and cancer cells.
Lee H, Paik SG
Molecules and cells. 2006 ; 21 (1) : 1-6.
PMID 16511341
 
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
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written10-2007Sang-Gi Paik, Hayyoung Lee
Department of Biology, School of Biosciences and Biotechnology, Chungnam National University, Daejeon 305-764, Korea.

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. October 2007 .
URL : http://AtlasGeneticsOncology.org/Genes/BNIP3ID822ch10q26.html

This paper is referenced by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/38517/1/10-2007-BNIP3ID822ch10q26.pdf   [ Bibliographic record ]

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indexed on : Sat Apr 28 15:05:06 CEST 2012

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