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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.

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Other aliasNIP3
LocusID (NCBI) 664
Atlas_Id 822
Location 10q26.3  [Link to chromosome band 10q26]
Location_base_pair Starts at and ends at bp from pter
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)


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).


  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


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


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 ]
On line version :

External links

Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)664
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
canSAR (ICR) (select the gene name)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Thu Oct 18 17:29:59 CEST 2018

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