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BNIP2  -  BCL2/adenovirus E1B 19kDa interacting...

Homo sapiens

Synonyms: BCL2/adenovirus E1B 19 kDa protein-interacting protein 2, BNIP-2, NIP2, Nip2
 
 
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Disease relevance of BNIP2

  • Here we report the identification of BNIP-2, a previously cloned Bcl-2- and adenovirus E1B-associated protein, as a putative substrate of the receptor [1].
  • When we compared lung adenomas, lung ACs, and normal lung parenchyma, 24 developmentally regulated genes were found aberrantly expressed in lung tumors; these included the cell cycle control factor CDC5, the cellular differentiation factor TEA domain 4, and the proapoptotic factor BNIP 2 [2].
 

High impact information on BNIP2

  • We have isolated cDNAs for three different proteins, designated Nip1, Nip2, and Nip3, that interact with the 19 kDa protein [3].
  • Treatment with E2 was also associated with a time-dependent decrease in the mRNA level of the proapoptotic Nip-2 protein, supporting the hypothesis that hormone responsiveness of U937 cells is mediated by target gene transcription [4].
  • Further time course analysis of PTMA and Nip2 mRNAs levels indicated that the hormone exerted a marked biphasic regulatory effect on expression of both messages during the course of cell differentiation [5].
  • The BNIP-2 and Cdc42GAP homology/Sec14p-like domain of BNIP-Salpha is a novel apoptosis-inducing sequence [6].
  • These observations led us to hypothesize an involvement of bnip2 in estrogen effects on cell survival [7].
 

Biological context of BNIP2

  • BNIPL-2, a novel homologue of BNIP-2, interacts with Bcl-2 and Cdc42GAP in apoptosis [8].
  • We recently identified BNIP-2, a previously cloned Bcl-2- and E1B-associated protein, as a putative substrate of the FGF receptor tyrosine kinase and showed that it possesses GTPase-activating activity toward Cdc42 despite the lack of homology to previously described catalytic domains of GTPase-activating proteins (GAPs) [9].
  • Investigations carried out in our laboratory proved a strong correlation between the increased expression of bnip2 gene and cell death induced by toxic stimuli [7].
  • Furthermore, we showed that transfection of the bnip2 cDNA results in massive cell death and Bcl-2 overexpression counteracts the toxic effect of bnip2 [7].
  • Bioinformatic analyses together with progressive deletional mutagenesis and binding studies revealed that a distal part of the BNIP-2 BCH domain contained a sequence with low homology to CRIB motif [10].
 

Anatomical context of BNIP2

  • We recently showed that BNIP-2 is a putative substrate of the fibroblast growth factor receptor tyrosine kinase and it possesses GTPase-activating activity toward the small GTPase, Cdc42 [11].
 

Associations of BNIP2 with chemical compounds

  • Its 350 kDa protein product possessed a Bcl2-/adenovirus E1B nineteen kDa-interacting protein 2 (BNIP2) and Cdc42GAP homology domain in the COOH-terminus in addition to P-loop and a coiled-coil region near the NH2-terminus [12].
  • From deletion studies, a region adjacent to the arginine patch ((288)EYV(290) on BNIP-2) and the Switch I and Rho family-specific "Insert" region on Cdc42 are involved in the binding [9].
  • The finding that bnip2 is developmentally regulated may suggest a role of this gene in those brain areas where the differentiation is orchestrated by estradiol [7].
  • Time-course experiments carried out in different cell systems and with a variety of neurotoxic agents proved a strong correlation between estrogen-induced decrease in bnip2 expression and the time required for estrogen to exert its protective effect [7].
 

Physical interactions of BNIP2

  • Site-directed mutagenesis confirmed that an R235K or R238K mutation severely impaired the BNIP-2 GAP activity without affecting its binding to Cdc42 [9].
  • Cells expressing the BNIP-2 mutants devoid of this motif or/and the 34-amino acids immediately upstream to this sequence failed to elicit cell elongation and membrane protrusions despite that the protein still remained in the cytoplasm and interacted with Cdc42GAP [10].
 

Regulatory relationships of BNIP2

  • Presence of the Cdc42/Rac1 interactive binding (CRIB) motif alone as the dominant negative mutant of p21-activated kinase also inhibited the BNIP-2 effect [10].
 

Other interactions of BNIP2

  • We found that the human BNIPL-2 shares homology to human BNIP-2 and also possesses a BNIP-2 and Cdc42GAP homology (BCH) domain [8].
  • BNIP-Salpha induces cell rounding and apoptosis by displacing p50RhoGAP and facilitating RhoA activation via its unique motifs in the BNIP-2 and Cdc42GAP homology domain [13].
  • Bcl-2/adenovirus E1B 19 kDa interacting protein 2-like, BNIP-2-like (BNIPL) is a recently cloned and characterized apoptosis-associated protein that shares 72% homology with BNIP-2 [14].

References

  1. Tyrosine phosphorylation of the Bcl-2-associated protein BNIP-2 by fibroblast growth factor receptor-1 prevents its binding to Cdc42GAP and Cdc42. Low, B.C., Lim, Y.P., Lim, J., Wong, E.S., Guy, G.R. J. Biol. Chem. (1999) [Pubmed]
  2. Molecular profiling of mouse lung tumors: association with tumor progression, lung development, and human lung adenocarcinomas. Bonner, A.E., Lemon, W.J., Devereux, T.R., Lubet, R.A., You, M. Oncogene (2004) [Pubmed]
  3. Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins. Boyd, J.M., Malstrom, S., Subramanian, T., Venkatesh, L.K., Schaeper, U., Elangovan, B., D'Sa-Eipper, C., Chinnadurai, G. Cell (1994) [Pubmed]
  4. Estrogen and progesterone induction of survival of monoblastoid cells undergoing TNF-alpha-induced apoptosis. Vegeto, E., Pollio, G., Pellicciari, C., Maggi, A. FASEB J. (1999) [Pubmed]
  5. Identification of estrogen-responsive genes in neuroblastoma SK-ER3 cells. Garnier, M., Di Lorenzo, D., Albertini, A., Maggi, A. J. Neurosci. (1997) [Pubmed]
  6. The BNIP-2 and Cdc42GAP homology/Sec14p-like domain of BNIP-Salpha is a novel apoptosis-inducing sequence. Zhou, Y.T., Soh, U.J., Shang, X., Guy, G.R., Low, B.C. J. Biol. Chem. (2002) [Pubmed]
  7. Estrogen neuroprotection: the involvement of the Bcl-2 binding protein BNIP2. Belcredito, S., Vegeto, E., Brusadelli, A., Ghisletti, S., Mussi, P., Ciana, P., Maggi, A. Brain Res. Brain Res. Rev. (2001) [Pubmed]
  8. BNIPL-2, a novel homologue of BNIP-2, interacts with Bcl-2 and Cdc42GAP in apoptosis. Qin, W., Hu, J., Guo, M., Xu, J., Li, J., Yao, G., Zhou, X., Jiang, H., Zhang, P., Shen, L., Wan, D., Gu, J. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  9. Evidence for a novel Cdc42GAP domain at the carboxyl terminus of BNIP-2. Low, B.C., Seow, K.T., Guy, G.R. J. Biol. Chem. (2000) [Pubmed]
  10. BNIP-2 induces cell elongation and membrane protrusions by interacting with Cdc42 via a unique Cdc42-binding motif within its BNIP-2 and Cdc42GAP homology domain. Zhou, Y.T., Guy, G.R., Low, B.C. Exp. Cell Res. (2005) [Pubmed]
  11. The BNIP-2 and Cdc42GAP homology domain of BNIP-2 mediates its homophilic association and heterophilic interaction with Cdc42GAP. Low, B.C., Seow, K.T., Guy, G.R. J. Biol. Chem. (2000) [Pubmed]
  12. Increased expression of proapoptotic BMCC1, a novel gene with the BNIP2 and Cdc42GAP homology (BCH) domain, is associated with favorable prognosis in human neuroblastomas. Machida, T., Fujita, T., Ooo, M.L., Ohira, M., Isogai, E., Mihara, M., Hirato, J., Tomotsune, D., Hirata, T., Fujimori, M., Adachi, W., Nakagawara, A. Oncogene (2006) [Pubmed]
  13. BNIP-Salpha induces cell rounding and apoptosis by displacing p50RhoGAP and facilitating RhoA activation via its unique motifs in the BNIP-2 and Cdc42GAP homology domain. Zhou, Y.T., Guy, G.R., Low, B.C. Oncogene (2006) [Pubmed]
  14. The apoptosis-associated protein BNIPL interacts with two cell proliferation-related proteins, MIF and GFER. Shen, L., Hu, J., Lu, H., Wu, M., Qin, W., Wan, D., Li, Y.Y., Gu, J. FEBS Lett. (2003) [Pubmed]
 
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