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Gene Review

BNIP3  -  BCL2/adenovirus E1B 19kDa interacting...

Homo sapiens

Synonyms: BCL2/adenovirus E1B 19 kDa protein-interacting protein 3, NIP3, Nip3
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Disease relevance of BNIP3


Psychiatry related information on BNIP3


High impact information on BNIP3

  • After transfection, both Nip3 and Nip3(163) protein levels decrease steadily over 48 h indicating that the protein is rapidly degraded and this occurs in the absence of cell death [7].
  • Bcl-2 overexpression initially delays the onset of apoptosis induced by Nip3 but the resistance is completely overcome in longer periods of incubation [7].
  • Nip3 is expressed in mitochondria and a mutant (Nip3(163)) lacking the putative transmembrane domain and COOH terminus does not dimerize or localize to mitochondria [7].
  • Transient transfection of epitope-tagged Nip3 in Rat-1 fibroblasts and MCF-7 breast carcinoma induces apoptosis within 12 h while cells transfected with the Nip3(163) mutant have a normal phenotype, suggesting that mitochondrial localization is necessary for induction of cell death [7].
  • Nip3 (nineteen kD interacting protein-3) is an E1B 19K and Bcl-2 binding protein of unknown function [7].

Chemical compound and disease context of BNIP3


Biological context of BNIP3


Anatomical context of BNIP3


Associations of BNIP3 with chemical compounds

  • Deletion of the BH3-like motif in BNIP3 abrogates its ability to heterodimerize with E1B-19K and BCL-xL [8].
  • The methylation status of CpG dinucleotides within the BNIP3 promoter was analyzed after bisulfite treatment by sequencing and methylation-specific PCR [3].
  • Deletion mapping of BNIP3 excluded its BH3-like domain and identified the NH(2) terminus (residues 1-49) and TM domain as critical for Bcl-2 heterodimerization, and either region was sufficient for Bcl-X(L) interaction [16].
  • Downregulation of BNIP3 resulted in increased resistance to 5-fluoro-uracil and gemcitabine [17].
  • Moreover, treating methylated cells with the methyltransferase inhibitor 5-aza-2'-deoxycytidine restored hypoxia-induced expression of BNIP3 mRNA and protein, which in turn led to cell death [18].
  • We demonstrate that hypoxia-reoxygenation and agents that activate protein kinase C, including calcium ionophore, phorbol 12-myristate 13-acetate, and okadaic acid, also induce Bnip3 [19].

Physical interactions of BNIP3

  • Furthermore, HIF-1alpha directly binds to a consensus HIF-1alpha-responsive element (HRE) in the human BNIP3 promoter that upon mutation of this HRE site eliminates the hypoxic responsiveness of the promoter [15].

Regulatory relationships of BNIP3


Other interactions of BNIP3

  • Using CD47 as bait in a yeast two-hybrid system, we identified the Bcl-2 homology 3 (BH3)-only protein 19 kDa interacting protein-3 (BNIP3), a pro-apoptotic member of the Bcl-2 family, as a novel partner [14].
  • Cellular protein BNIP3 is a BCL-2 family proapoptotic protein that interacts with viral antiapoptosis proteins such as adenoviruses E1B-19K and EBV-BHRF1 and cellular antiapoptosis proteins such as BCL-2 and BCL-xL [11].
  • Substitution of the BH3 domain of BNIP3 for the corresponding sequences of BAX functionally restores the pro-apoptotic and protein heterodimerization activities of BAX [8].
  • HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors [1].
  • Overexpression of HIF1alpha, but not p53, induces the expression of BNIP3 [23].

Analytical, diagnostic and therapeutic context of BNIP3


  1. HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Sowter, H.M., Ratcliffe, P.J., Watson, P., Greenberg, A.H., Harris, A.L. Cancer Res. (2001) [Pubmed]
  2. Paeoniae Radix, a Chinese herbal extract, inhibit hepatoma cells growth by inducing apoptosis in a p53 independent pathway. Lee, S.M., Li, M.L., Tse, Y.C., Leung, S.C., Lee, M.M., Tsui, S.K., Fung, K.P., Lee, C.Y., Waye, M.M. Life Sci. (2002) [Pubmed]
  3. Silencing of the hypoxia-inducible cell death protein BNIP3 in pancreatic cancer. Okami, J., Simeone, D.M., Logsdon, C.D. Cancer Res. (2004) [Pubmed]
  4. Bnip3 mediates the hypoxia-induced inhibition on mammalian target of rapamycin by interacting with Rheb. Li, Y., Wang, Y., Kim, E., Beemiller, P., Wang, C.Y., Swanson, J., You, M., Guan, K.L. J. Biol. Chem. (2007) [Pubmed]
  5. BNIP3 as a progression marker in primary human breast cancer; opposing functions in in situ versus invasive cancer. Tan, E.Y., Campo, L., Han, C., Turley, H., Pezzella, F., Gatter, K.C., Harris, A.L., Fox, S.B. Clin. Cancer Res. (2007) [Pubmed]
  6. cDNA array reveals mechanosensitive genes in chondrocytic cells under hydrostatic pressure. Sironen, R.K., Karjalainen, H.M., Elo, M.A., Kaarniranta, K., Törrönen, K., Takigawa, M., Helminen, H.J., Lammi, M.J. Biochim. Biophys. Acta (2002) [Pubmed]
  7. 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, R.C., Saxena, S., Gietz, R.D., Greenberg, A.H. J. Exp. Med. (1997) [Pubmed]
  8. 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. J. Biol. Chem. (1998) [Pubmed]
  9. Intestinal and hepatic expression of BNIP3 in necrotizing enterocolitis: regulation by nitric oxide and peroxynitrite. Zamora, R., Vodovotz, Y., Betten, B., Wong, C., Zuckerbraun, B., Gibson, K.F., Ford, H.R. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  10. Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Daido, S., Kanzawa, T., Yamamoto, A., Takeuchi, H., Kondo, Y., Kondo, S. Cancer Res. (2004) [Pubmed]
  11. BNIP3alpha: a human homolog of mitochondrial proapoptotic protein BNIP3. Yasuda, M., Han, J.W., Dionne, C.A., Boyd, J.M., Chinnadurai, G. Cancer Res. (1999) [Pubmed]
  12. Cloning of BNIP3h, a member of proapoptotic BNIP3 family genes. Farooq, M., Kim, Y., Im, S., Chung, E., Hwang, S., Sohn, M., Kim, M., Kim, J. Exp. Mol. Med. (2001) [Pubmed]
  13. 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, A.H. Mol. Cell. Biol. (2000) [Pubmed]
  14. CD47 and the 19 kDa interacting protein-3 (BNIP3) in T cell apoptosis. Lamy, L., Ticchioni, M., Rouquette-Jazdanian, A.K., Samson, M., Deckert, M., Greenberg, A.H., Bernard, A. J. Biol. Chem. (2003) [Pubmed]
  15. BNIP3 plays a role in hypoxic cell death in human epithelial cells that is inhibited by growth factors EGF and IGF. Kothari, S., Cizeau, J., McMillan-Ward, E., Israels, S.J., Bailes, M., Ens, K., Kirshenbaum, L.A., Gibson, S.B. Oncogene (2003) [Pubmed]
  16. 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, J.H., Reed, J.C., Gietz, R.D., Greenberg, A.H. J. Biol. Chem. (2000) [Pubmed]
  17. 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, M.W., Giese, N.A., Friess, H. Oncogene (2005) [Pubmed]
  18. 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. Clin. Cancer Res. (2005) [Pubmed]
  19. Regulation of Bnip3 death pathways by calcium, phosphorylation, and hypoxia-reoxygenation. Graham, R.M., Thompson, J.W., Wei, J., Bishopric, N.H., Webster, K.A. Antioxid. Redox Signal. (2007) [Pubmed]
  20. Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Bruick, R.K. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  21. Upregulation of BNIP3 promotes apoptosis of lung cancer cells that were induced by p53. Yan, J., Yun, H., Yang, Y., Jing, B., Feng, C., Song-bin, F. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  22. Selective silencing of the hypoxia-inducible factor 1 target gene BNIP3 by histone deacetylation and methylation in colorectal cancer. Bacon, A.L., Fox, S., Turley, H., Harris, A.L. Oncogene (2007) [Pubmed]
  23. Hypoxia induces the expression of the pro-apoptotic gene BNIP3. Guo, K., Searfoss, G., Krolikowski, D., Pagnoni, M., Franks, C., Clark, K., Yu, K.T., Jaye, M., Ivashchenko, Y. Cell Death Differ. (2001) [Pubmed]
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