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

2007-10-01   Sang-Gi Paik , Hayyoung Lee 

Department of Biology, School of Biosciences, Biotechnology, Chungnam National University, Daejeon 305-764, Korea.




Atlas Image


14.23 kb on reverse strand; 6 exons


mRNA in MCF-7 cells are 1.7kb (major) and 1.5 kb (minor) and 1.3 kb (minor).


Atlas Image
Domain map of BNIP3 protein; BH3 domain (Bcl-2 holomogy 3 domain); TM domain (transmembrane domain)


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.


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.


Outer mitochondrial membrane


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.


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 name
Pancreatic cancer
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.
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 name
Colorectal cancer
Methylation of BNIP3 in 66% of primary colorectal cancer


Pubmed IDLast YearTitleAuthors
159427162005Upregulation of BNIP3 by 5-aza-2'-deoxycytidine sensitizes pancreatic cancer cells to hypoxia-mediated cell death.Abe T et al
158377652005Intrinsic chemoresistance to gemcitabine is associated with decreased expression of BNIP3 in pancreatic cancer.Akada M et al
169542132006Activation of Ras up-regulates pro-apoptotic BNIP3 in nitric oxide-induced cell death.An HJ et al
167996362007Selective silencing of the hypoxia-inducible factor 1 target gene BNIP3 by histone deacetylation and methylation in colorectal cancer.Bacon AL et al
79548001994Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins.Boyd JM et al
109220632000Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia.Bruick RK et al
93967661997The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis.Chen G et al
158560262005Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis.Erkan M et al
118318442002The carboxy terminal C-tail of BNip3 is crucial in induction of mitochondrial permeability transition in isolated mitochondria.Kim JY et al
122264792002Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3.Kubasiak LA et al
165113412006Regulation of BNIP3 in normal and cancer cells.Lee H et al
157091672005Aberrant methylation and silencing of the BNIP3 gene in colorectal and gastric cancer.Murai M et al
152893402004Silencing of the hypoxia-inducible cell death protein BNIP3 in pancreatic cancer.Okami J et al
106256962000BNIP3 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 et al
108914862000BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore.Vande Velde C et al
156234202005BNip3 and signal-specific programmed death in the heart.Webster KA et al
95751971998Adenovirus E1B-19K/BCL-2 interacting protein BNIP3 contains a BH3 domain and a mitochondrial targeting sequence.Yasuda M et al
153581752004Nitric oxide induces BNIP3 expression that causes cell death in macrophages.Yook YH et al

Other Information

Locus ID:

NCBI: 664
MIM: 603293
HGNC: 1084
Ensembl: ENSG00000176171


dbSNP: 664
ClinVar: 664
TCGA: ENSG00000176171


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Autophagy - animalKEGGko04140
Autophagy - animalKEGGhsa04140
FoxO signaling pathwayKEGGhsa04068
Mitophagy - animalKEGGko04137
Mitophagy - animalKEGGhsa04137

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
192735852009Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains.426
225057142012Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy.187
175768132007BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy.162
185511302008Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L.115
180591692008Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3.114
232092952013Modulation of serines 17 and 24 in the LC3-interacting region of Bnip3 determines pro-survival mitophagy versus apoptosis.102
179282952007Bnip3 mediates the hypoxia-induced inhibition on mammalian target of rapamycin by interacting with Rheb.93
173603632007Legionella pneumophila inhibits macrophage apoptosis by targeting pro-death members of the Bcl2 protein family.90
152893402004Silencing of the hypoxia-inducible cell death protein BNIP3 in pancreatic cancer.76
158560262005Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis.68


Sang-Gi Paik ; Hayyoung Lee

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

Atlas Genet Cytogenet Oncol Haematol. 2007-10-01

Online version: