Nitric oxide induces BNIP3 expression that causes cell death in macrophages.
Nitric oxide (NO) is involved in many physiological processes and also causes pathological effects by inducing apoptosis. It can enhance or suppress apoptosis depending on its concentration and the cell type involved. In this report, we used cDNA microarray analysis to show that SNAP, an NO donor, strongly induces Bcl-2/adenovirus E1B 19kDa-interacting protein 3 (BNIP3) in macrophages. BNIP3 is a mitochondrial pro-apoptotic protein that contains a Bcl-2 homology 3 domain and a COOH-terminal transmembrane (TM) domain. Macrophages activated by LPS/IFN-gamma produce nitric oxide synthase 2 (NOS2) and release endogenous NO. Expression of BNIP3 was also induced in macrophages by LPS/IFN-gamma, and the induction was blocked by a NOS2 inhibitor, S-methyl-isothiourea. Peritoneal macrophages from NOS2-null mice failed to produce BNIP3 in response to LPS/IFN-gamma. We conclude that BNIP3 expression in macrophages is controlled by the intracellular level of nitric oxide. Overexpression of BNIP3 but not of BNIP3 deltaTM, a BNIP3 mutant without the TM domain and C-terminal tail, led to apoptosis of the cells. Promoter analysis showed that the region between -281 and -1 of the 5'-upstream enhancer region of murine BNIP3 was sufficient for NO-dependent expression of BNIP3.
Yook
Young-Hun
YH
Department of Biology, Chungnam National University, Daejeon, Republic of Korea.
Kang
Kyoung-Hee
KH
Maeng
Oky
O
Kim
Tae-Rim
TR
Lee
Jie-Oh
JO
Kang
Kwang-il
KI
Kim
Young Sang
YS
Paik
Sang-Gi
SG
Lee
Hayyoung
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics
C090121:BNIP3 protein, human; D008246:Lysophospholipids; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase