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

Identity

Other names	NIP3
HGNC	BNIP3
Location	10q26.3
Location_base_pair	Starts at 133631194 and ends at 133645425 bp from pter ( according to hg18-Mar_2006).

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.
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	BNIP3   1084
Entrez_Gene	BNIP3  664  BCL2/adenovirus E1B 19kDa interacting protein 3
	Cards
Atlas	BNIP3ID822ch10q26
GeneCards	BNIP3
Ensembl	ENSG00000176171 [Gene_View]  BNIP3 [Vega]
Genatlas	BNIP3
	Genomic and cartography
GoldenPath	BNIP3  -  10q26.3   chr10:133631194-133645425 -  10q26.3   [Description]    (hg18-Mar_2006)
Ensembl	BNIP3 - 10q26.3 [CytoView]
NCBI	Mapview
OMIM	603293 Disease map [OMIM]
HomoloGene	BNIP3
	Gene and transcription
Genbank	AF002697 [ ENTREZ ]
Genbank	AK222626 [ ENTREZ ]
Genbank	BC009342 [ ENTREZ ]
Genbank	BC021989 [ ENTREZ ]
Genbank	BC067818 [ ENTREZ ]
RefSeq	NM_004052 [ SRS ]    NM_004052 [ ENTREZ ]
RefSeq	AC_000053 [ SRS ]    AC_000053 [ ENTREZ ]
RefSeq	AC_000142 [ SRS ]    AC_000142 [ ENTREZ ]
RefSeq	NC_000010 [ SRS ]    NC_000010 [ ENTREZ ]
RefSeq	NT_017795 [ SRS ]    NT_017795 [ ENTREZ ]
RefSeq	NW_001838014 [ SRS ]    NW_001838014 [ ENTREZ ]
RefSeq	NW_924884 [ SRS ]    NW_924884 [ ENTREZ ]
CCDS	BNIP3 CCDS - NCBI
AceView	BNIP3 AceView - NCBI
Unigene	Hs.144873 [ SRS ]    Hs.144873 [ NCBI ]
Fast-db	17100 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q12983 [ SRS]    Q12983 [ EXPASY ]     Q12983 [ INTERPRO ]     Q12983 [ UNIPROT ] Q12983 [ VarSplice FASTA ]
Interpro	IPR010548 BNIP3 [ SRS ]    IPR010548 BNIP3 [ EBI ]
CluSTr	Q12983
Pfam	PF06553 BNIP3 [ SRS ]    PF06553 BNIP3 [ Sanger ]    pfam06553 [ NCBI-CDD ]
Blocks	Q12983
PDB	2J5D [ SRS ]    2J5D [ PdbSum ],   2J5D [ IMB ]   2J5D [ RSDB ]
HPRD	04482
	Protein Interaction databases
DIP	Q12983
IntAct	Q12983
	Polymorphism : SNP, mutations, diseases
OMIM	603293    [ map ]
GENETests	603293
SNP	BNIP3 [dbSNP-NCBI]
SNP	NM_004052 [SNP-NCI]
SNP	BNIP3 [GeneSNPs - Utah]  BNIP3] [HGBASE - SRS]
HAPMAP	BNIP3 [HAPMAP]
COSMIC	BNIP3 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	BNIP3
Genetic Association	BNIP3
CDC HuGE	BNIP3
	General knowledge
Family Browser	BNIP3 [UCSC Family Browser]
SOURCE	NM_004052
SMD	Hs.144873
SAGE	Hs.144873
GO	response to hypoxia [Amigo]  response to hypoxia
GO	nucleus [Amigo]  nucleus
GO	nuclear envelope [Amigo]  nuclear envelope
GO	nucleoplasm [Amigo]  nucleoplasm
GO	cytoplasm [Amigo]  cytoplasm
GO	mitochondrion [Amigo]  mitochondrion
GO	mitochondrion [Amigo]  mitochondrion
GO	DNA fragmentation during apoptosis [Amigo]  DNA fragmentation during apoptosis
GO	chromatin remodeling [Amigo]  chromatin remodeling
GO	oxygen and reactive oxygen species metabolic process [Amigo]  oxygen and reactive oxygen species metabolic process
GO	anti-apoptosis [Amigo]  anti-apoptosis
GO	induction of apoptosis [Amigo]  induction of apoptosis
GO	cell death [Amigo]  cell death
GO	cell death [Amigo]  cell death
GO	negative regulation of survival gene product expression [Amigo]  negative regulation of survival gene product expression
GO	membrane [Amigo]  membrane
GO	integral to membrane [Amigo]  integral to membrane
GO	dendrite [Amigo]  dendrite
GO	integral to mitochondrial outer membrane [Amigo]  integral to mitochondrial outer membrane
GO	mitochondrial membrane [Amigo]  mitochondrial membrane
GO	mitochondrial membrane [Amigo]  mitochondrial membrane
GO	protein homodimerization activity [Amigo]  protein homodimerization activity
GO	interspecies interaction between organisms [Amigo]  interspecies interaction between organisms
GO	negative regulation of membrane potential [Amigo]  negative regulation of membrane potential
GO	regulation of mitochondrial membrane permeability [Amigo]  regulation of mitochondrial membrane permeability
GO	protein heterodimerization activity [Amigo]  protein heterodimerization activity
GO	neuron apoptosis [Amigo]  neuron apoptosis
GO	defense response to virus [Amigo]  defense response to virus
PubGene	BNIP3
TreeFam	BNIP3
CTD	664 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	BNIP3 Related clones (RZPD - Berlin)
	PubMed
PubMed	45 Pubmed reference(s) in Entrez

Bibliography

Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins.

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The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis.

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Adenovirus E1B-19K/BCL-2 interacting protein BNIP3 contains a BH3 domain and a mitochondrial targeting sequence.

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Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia.

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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

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PMID 10625696

BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore.

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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

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Contributor(s)

Written	10-2007	Sang-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

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Thu Nov 27 13:20:23 2008