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J. Biol. Chem., Vol. 281, Issue 45, 33939-33948, November 10, 2006

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Activation of Ras Up-regulates Pro-apoptotic BNIP3 in Nitric Oxide-induced Cell Death^*

Hyun-Jung An, Oky Maeng, Kyoung-Hee Kang, Jie-Oh Lee, Young-Sang Kim^¶, Sang-Gi Paik¹, and Hayyoung Lee^||2

From the Departments of Biology and ^¶Biochemistry, School of Biosciences and Biotechnology, and the ^||Institute of Biotechnology, Chungnam National University, Daejeon 305-764, Korea and the Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea

Nitric oxide (NO) produced by NO synthases causes nitration and nitrosylation of cellular factors. We have shown previously that endogenously produced or exogenously added NO induces expression of BNIP3 (Bcl-2/adenovirus E1B 19kDa-interacting protein 3), leading to death of macrophages (Yook, Y.-H., Kang, K.-H., Maeng, O., Kim, T.-R., Lee, J.-O., Kang, K.-i., Kim, Y.-S., Paik, S.-G., and Lee, H. (2004) Biochem. Biophys. Res. Commun. 321, 298–305). We now provide evidence that Ras mediates NO-induced BNIP3 expression via the MEK/ERK/hypoxia-inducible factor (HIF)-1 pathway. (a) ras-Q61L, a constitutively active form of Ras, up-regulated BNIP3 protein expression by enhancing Bnip3 promoter activity, and ras-S17N, a dominant-negative form, and ras-C118S, an S-nitrosylation mutant, blocked NO-induced BNIP3 expression, suggesting that Ras acts downstream of NO and that NO activates Ras by nitrosylation. (b) U0126, a specific MEK inhibitor, completely abolished BNIP3 expression and the stimulation of promoter activity by NO and Ras, whereas 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, SB203580, and wortmannin, specific inhibitors of soluble guanylyl cyclase, p38 MAPK, and phosphatidylinositol 3-kinase, respectively, had no effect. Ras, MEK1/2, and ERK1/2 were sequentially activated by NO treatment of macrophages. (c) Mutation of the HIF-1-binding site (hypoxia-response element) in the Bnip3 promoter abolished BNIP3 induction, and HIF-1 was strongly induced by NO. (d) Transient expression of activated Ras promoted macrophage death, as did NO, and this Ras-mediated cell death was inhibited by silencing BNIP3 expression. These results suggest that NO-induced death of macrophages is mediated, at least in part, by BNIP3 induction.

Received for publication, June 19, 2006 , and in revised form, September 1, 2006.

^* This work was supported by Korea Research Foundation Grant KRF-2004-005-C00169 and the Brain Korea 21 Project (to H.-J. A. and H. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed. Tel.: 82-42-821-5496; Fax: 82-42-822-9690; E-mail: sgpaik{at}cnu.ac.kr. ² To whom correspondence may be addressed. Tel.: 82-42-821-7533; Fax: 82-42-822-9690; E-mail: hlee{at}cnu.ac.kr.

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