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Nrh, a Human Homologue of Nr-13 Associates with Bcl-Xs and Is an Inhibitor of Apoptosis

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Nrh, a Human Homologue of Nr-13 Associates with Bcl-Xs and Is an Inhibitor of Apoptosis Oncogene (2001) 20, 5846 ± 5855 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Nrh, a human homologue of Nr-13 associates with Bcl-Xs and is an inhibitor of apoptosis Abdel Aouacheria1,4, Estelle Arnaud1,4,Se verine Venet1, Philippe Lalle1, Manolo Gouy2, Dominique Rigal3 and Germain Gillet*,1 1Institut de Biologie et Chimie des ProteÂines, UMR 5086 CNRS/Universite Claude Bernard, 7 passage du Vercors, F69367 Lyon cedex 07, France; 2BiomeÂtrie et Biologie Evolutive, UMR 5558 CNRS/Universite Claude Bernard, 43 Boulevard du 11 novembre, F69622 Villeurbanne cedex, France; 3Etablissement de Transfusion Sanguine, passage du Vercors, F 69007 Lyon, France In search of human homologues of the anti-apoptotic dated. In particular, it has been established that in protein Nr-13, we have characterized a human EST most cases, apoptosis is due to irreversible activation of clone that potentially encodes a protein, which is the a cascade of particular cysteine proteases (caspases) closest homologue of Nr-13 among the Bcl-2 family which cleave their targets at the level of aspartate members, to date known, in humans. Phylogenetic residues (Henkart, 1996). A central event, which leads analyses suggest Human nrh, Mouse diva/boo and Quail to caspase activation is the release of cytochrome c nr-13 to be orthologous genes. The nrh gene has the from mitochondria into the cytoplasm (Kroemer et al., same overall organization as nr-13 and diva/boo with one 1997). Although the exact mechanisms monitoring single intron interrupting the ORF at the level of the Bcl- cytochrome c subcellular localization are still partly 2-homology domain BH2. RT ± PCR-based analysis of unknown, a number of reports support the notion that nrh expression indicated that this gene is preferentially a decrease in the mitochondrial transmembrane expressed in the lungs, the liver and the kidneys. potential (DcM) observed in early steps of the Interestingly, two in frame ATG codons can lead apoptotic response is responsible for the release of potentially to the synthesis of two products, one of them cytochrome c into the cytoplasm (Kroemer et al., 1997; lacking 10 aminoacids at the N-terminal end. Sequence Zhivotovsky et al., 1998; Martinou, 1999). The Bcl-2 alignment with Nr-13 and Diva/Boo in addition to family of inhibitors of apoptosis may act by stabilizing secondary structure prediction of the nrh transcript cytochrome c interactions with the inner mitochondrial suggested that the shortest protein will be preferentially membrane thus preventing the activation of caspases synthetized. Immunohistochemical analyses have revealed (Kluck et al., 1997; Rosse et al., 1998). These proteins that Nrh is associated with mitochondria and the nuclear show four homology domains (BH1-4) forming a- envelope. Moreover, Nrh preferentially associates with helices (Kelekar and Thompson, 1998). BH1 and BH2 the apoptosis accelerator Bcl-Xs and behaves as an domains exhibit the highest degree of conservation inhibitor of apoptosis both in yeast and vertebrate cells. throughout the family. All inhibitors of apoptosis Oncogene (2001) 20, 5846 ± 5855. possess the four BH domains. In contrast a number of apoptosis accelerators lack the BH4 domain, a Keywords: apoptosis; molecular cloning; Bcl-2 family; subgroup of apoptosis accelerators even possessing phylogeny only the BH3 domain. These proteins can interact with the outer mitochondrial membrane via their hydro- phobic C-terminal region (Nguyen et al., 1993; Introduction Krajewski et al., 1993; Yang et al., 1995). In addition, structural data have revealed that they may share Apoptosis is a self destruction event leading to the functional properties with pore-forming bacterial elimination of unwanted cells from multicellular colicins (Muchmore et al., 1996). Indeed, although in organisms. In developing embryo, apoptosis plays a conditions which seem far from physiological situa- key role in tissue morphogenesis. In adults it tions, Bcl-2 can form pores in arti®cial membranes participates in tissue homeostasis. Deregulation of (Schlesinger et al., 1997; Minn et al., 1997). The pore apoptosis leads to degenerative disorders or cancers forming domain has been identi®ed and corresponds to (Thompson, 1995). During the last decade, the basic two amphipatic helices, which are conserved among the molecular mechanisms of apoptosis have been eluci- Bcl-2 family (Matsuyama et al., 1998). In addition to their ability to interact with the bilayer, Bcl-2 proteins participate in a network of interactions between cellular proteins, which may or may not belong to *Correspondence: G Gillet; E-mail: [email protected] the Bcl-2 family. For example Bcl-2 can interact with 4The ®rst two authors contributed equally to this work Received 17 April 2001; revised 11 June 2001; accepted 18 June Bax, a Bcl-2 homologue having pro-apoptotic proper- 2001 ties and with the mitochondrial proteins VDAC- A human homologue of the anti-apoptotic protein Nr-13 A Aouacheria et al 5847 voltage-dependent anion channel- and ANT-adenosine anti-apoptotic members of the bcl-2 family (Figure 1). nucleotide translocator- (Otter et al., 1998; Shimizu et The genomic organization of chicken Nr-13 and mouse al., 1999; Brenner et al., 2000). In addition to Diva/Boo has been determined (our unpublished mitochondrial proteins, Bcl-2 interacts with numerous results). Comparison with Nrh shows that these three partners such as calcineurin (Shibasaki et al., 1997), the genes share the same organization with one single kinase Raf-1 (Wang et al., 1994) and the transcrip- intron located at the same position. In silico screening tional repressor Btf (Kasof et al., 1999). However, the of the human genome revealed that Nrh is a single exact nature of these interactions remain unclear. copy gene located on chromosome 15 (locus 15q21), in Nevertheless, the combination of the above data the vicinity of several Mittelman breakpoints, accord- suggest together that Bcl-2 proteins are at the cross ing to the NCBI database. road between mitochondria and cell signalling path- Since the EST clone lacked part of the ORF, a ways, which directly or indirectly participate in the human genomic library was screened to obtain a control of cell survival. genomic clone containing the missing sequence. One The anti- and pro-apoptotic members of the Bcl-2 clone containing the entire 1st exon has been isolated. family are respectively potential oncogenes and tumour Nrh ORF was then reconstructed using a PCR-based suppressors. Indeed, a number of cancer cells express strategy and the EST and genomic clones as templates. inhibitors of cell death or down regulate expression of apoptosis accelerators (Reed et al., 1988; Li and Dou, 2000). Tumors overexpressing inhibitors of apoptosis of the Bcl-2 family often exhibit strong resistance to anticancer drugs (Walczak et al., 2000; Yang et al., 2000). Actually these proteins are key actors in oncogenesis and resistance to chemotherapy. In this context, identi®cation of new Bcl-2-related sequences is thus essential for a detailed understanding of apoptosis control and can be of considerable therapeutic interest for humans. We describe, here, the molecular cloning and characterization of a new inhibitor of apoptosis in humans. This protein (Nrh, for Nr-13 human), which possesses the four Bcl-2 homology domains BH1-4, is the closest human homologue of the avian protein Nr- 13, involved in tumour formation following infection by the Rous sarcoma virus (Gillet et al., 1993, 1995; Mangeney et al., 1996). Moreover, we show that Nrh interacts strongly with Bcl-Xs and counteracts its death-inducing eect. Finally, detection of Nrh both at the level of mitochondria and nuclear membrane, suggests that it may participate both in the control of mitochondria activity and of nucleocytoplasmic traf- ®cking. Results Molecular cloning and characterization of Nrh, a human homologue of avian Nr-13 and murine Diva/Boo Computer-assisted screening of public human EST databases led to the selection of clone #AA005293. This clone has a partial open reading frame potentially Figure 1 Genomic organization of nrh. Open reading frame and corresponding to a product having signi®cant homo- ¯anking sequences of nrh. Two potential in frame ATG initiator logies with the avian anti-apoptotic protein Nr-13 and codons are shown in bold characters. The presence of an inverted the mouse protein Diva/Boo. Comparison with the repeat allows the formation of a hairpin loop (shaded), suggesting human genome sequence available at NCBI indicated that the downstream ATG is the main initiator codon. The deduced aminoacid sequence starting at the second ATG is shown the entire ORF actually encodes a new Bcl-2 family below the nucleotidic sequence (block letters, one letter code). member of 194 amino acids exhibiting the typical Position of the intron with splice donor and splice acceptor sites is homology domains BH1 ± 4 and C-terminal transmem- indicated (italics). The polyadenylation site (boxed) and the polyA brane domain predicted by hydrophobicity pro®le tail are shown. Below the genomic sequence a diagram analysis. The organization of this new gene shows summarizes the overall organization of nrh, showing the intron and the conserved functional domains of the protein encoded by one single intron which splits the ORF within the BH2 the two exons, together with the conserved a1±a7 helices present region, i.e. at a location which is conserved among in inhibitors of apoptosis Oncogene A human homologue of the anti-apoptotic protein Nr-13 A Aouacheria et al 5848 Expression of nrh transcript was determined by PCR carried out on commercially available cDNAs obtained from human tissues. Figure 2 shows that nrh is preferentially expressed in adults in the lungs, the a liver, and the kidneys. Multiple alignments (Clustal W software) of the various Bcl-2 family members clearly show that Nrh has the highest homology with avian Nr-13 among the human Bcl-2-like sequences (25% identical residues and 28% similar residues, i.e.
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