Regulation of MAP kinase-dependent apoptotic pathway: implication of reactive oxygen and nitrogen species

Archives of Biochemistry and Biophysics 436 (2005) 406–412 www.elsevier.com/locate/yabbi

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Regulation of MAP kinase-dependent apoptotic pathway: implication of reactive oxygen and nitrogen species Vadim V. Sumbayev ¤, Inna M. Yasinska Department of Biochemistry, Mechnikov Odessa National University, Odessa, Ukraine Received 22 January 2005, and in revised form 10 February 2005

Abstract Mitogen-activated protein (MAP) kinase signaling cascades are multi-functional signaling networks that inXuence cell growth, diVerentiation, apoptosis, and cellular responses to stress. Apoptosis signal-regulating kinase 1 (ASK1) is a MAP kinase kinase kinase that triggers apoptogenic kinase cascade leading to the phosphorylation/activation of c-Jun N-terminal kinases and p38-MAP kinase, which are responsible for inducing apoptotic cell death. This pathway plays a pivotal role in transduction of signals from diVerent apoptotic stimuli. In the present review, we summarized the recent evidence concerning MAP kinase-dependent apoptotic pathway and its regulation in the mammalian cells and organism in vivo. We have shown that the key messengers of regulation of this pathway are the reactive oxygen and nitrogen species. The role of protein oxidation and S-nitrosation in induction of apoptotic cell death via ASK1 is discussed. Also we have outlined other recently discovered signal transduction processes involved in the regulation of ASK1 activity and downstream pathway.  2005 Elsevier Inc. All rights reserved. Keywords: Apoptosis; Cancer; MAP kinase cascades; Reactive oxygen and nitrogen species; Hypoxia

The mitogen-activated protein (MAP)1 kinase cascades are multi-functional signaling pathways that are evolutionally well conserved in all eukaryotic cells. Three MAP kinase cascades that converge on extracellular signal-regulating kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38 MAP kinases have already been characterized [1,2]. Based on the substrate protein, each of them consists of three types of kinases, MAP kinase, ¤ Corresponding author. Present address: Department of Molecular Biology, University of Aarhus, Gustav Wieds Vej 10 C, 8000 Aarhus C, Denmark. E-mail address: [email protected] (V.V. Sumbayev). 1 Abbreviations used: MAP, mitogen-activated protein; ERKs, extracellular signal-regulating kinases; JNKs, c-Jun N-terminal kinases; ASK1, apoptosis signal-regulating kinase 1; MKK, MAP kinase kinase; PARP, poly-(ADP-ribose)-polymerase; GSNO, S-nitrosoglutathione; NADPH, nicotinamide adenine dinucleotide phosphate; DPI, diphenyleniodonium; AEBSF, 4-(2-aminoethyl)-benzenesulfonyl Xuoride; ERE, estrogen responsive element; SNAP, S-nitroso-N-acetylpenicillamine.

0003-9861/$ - see front matter  2005 Elsevier Inc. All rights reserved. doi:10.1016/j.abb.2005.02.021

MAP kinase kinase (MKK), and MKK kinase (MKKK) [1]. MKKK phosphorylates and thereby activates MKK, which then causes an activation of MAP kinase by sitespeciWc phosphorylation. Two among those three MAP kinase cascades converge on JNKs and p38 MAP kinases are preferentially activated by cytotoxic stresses, such as X-ray/UV irradiation, heat/osmotic shock, and oxidative/nitrosative stress as well as by proinXammatory cytokines such as tumor necrosis factor
(TNF
) and interleukin-1 (IL-1). One of the crucial biological responses mediated by stress activated MAP kinase pathways appears to be the decision of cell fate by regulating apoptosis [1,3–8]. Apoptosis signal-regulating kinase 1 (ASK1)/ MKKK5 is a ubiquitously expressed enzyme that activates JNK and p38 MAP kinase pathways by direct sitespeciWc Ser/Thr phosphorylation of their respective MKKs—MKK4/MKK7 for JNK and MKK3/MKK6 for p38 MAP kinases
/. Activated MKKs perform

V.V. Sumbayev, I.M. Yasinska / Archives of Biochemistry and Biophysics 436 (2005) 406–412 Table 1 ASK1 downstream cascade and the kinase phosphorylation target sites Kinase

Substrates

Amino acid targets for phosphorylation

ASK1

MKK4 MKK7 MKK3 MKK6

Ser (S) 257, Thr (T) 261 Ser (S) 206, Thr (T) 210 Ser (S) 189, Thr (T) 193 Ser (S) 207, Thr (T) 211

MKK4

JNK

Thr (T) 183, Tyr (Y) 185

MKK7

JNK

Thr (T) 183, Tyr (Y) 185

MKK3

p38


Thr (T) 180, Tyr (Y) 182

MKK6

p38

Thr (T) 183, Tyr (Y) 185

Thr-X-Tyr phosphorylation of their target MAP kinases thereby activating them (Table 1) [3,9–12]. Activated JNK and p38 perform Ser/Thr phosphorylation of c-Jun inducing transcription factor and ATF-2. Jun protein could be either homo- or heterodimerized with ATF-2, respectively, forming Jun-Jun or Jun-ATF2 complex activator protein-1 (AP1) [10,13–17]. On the other hand, there was obtained clear evidence that nonphosphorylated JNK is complexed to p53 causing its ubiquitination followed by proteasomal degradation. JNK phosphorylation by MKK4/7 mediates dissociation of p53 followed by its stabilization [14,15]. p53 in combination with AP-1 leads to Bid cleavage followed by the translocation of Bax protein into mitochondria,

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which results in cytochrome c release and activation of caspase-3 by a widely described mechanism [10,13– 15,18] (Fig. 1). Recent studies have indicated that mitochondria also contain ASK1, which was found to mediate cytochrome c release by an unknown mechanism that does not assume activation of known MAP kinases [19].

Regulation of ASK1 and downstream pathway: the role of reactive oxygen (ROS) and nitrogen (RNS) species ASK1 was discovered as a 154.715 kDa protein, which consists of 1375 (mouse) or 1379 (human) amino acid residues. ASK1 is ubiquitously expressed in most of mammalian cells, however it is normally inhibited by thioredoxin (Trx)—12 kDa protein ubiquitously expressed in all living cells, which has a variety of biological functions related to cell proliferation and apoptosis [20,21]. It is characterized by the reduction/oxidation active site sequence Trp-Cys-Gly-Pro-Cys-Lys, which is conserved through evolution. Two cysteine residues within the redox active site provide the sulfhydryl groups involved in Trx reducing activity and ASK1 inhibition [20,21]. Trx interacts with ASK1 forming protein–protein complex. When Trx is bound to ASK1, the enzyme is inactivated and ubiquitously degraded [22]. For Trx-ASK1 binding, the reactive SH-groups of Trx must be in the

Fig. 1. Apoptotic pathways induced by ASK1 with diVerent localization in the cell [19].

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reduced form [22]. This scenario also applies to the ASK1 in mitochondria, where the enzyme activity is inhibited by Trx-2 [19]. Upon oxidation of Trx reactive thiol groups ASK1 was found to dissociate from Trx, followed by its activation, which includes three steps (in cytosol, but not in mitochondria, where the activation mechanism is not well described). First step assumes homodimerization of ASK1 followed by autophosphorylation of Thr845 in one of the monomers. Thr845 of another enzyme monomer is also phosphorylated by unknown kinase, which is however diVerent from ASK1. Homodimerized and phosphorylated ASK1 recruits homodimer TRAF2—tumor necrosis factor receptor associated factor 2. This protein complex is known to activate MKKs [23]. The ASK1 protein contains three domains—Trxbinding (amino acid residues 1–676), kinase domain (amino acid residues 677–935), and TRAF-2-binding (amino acid residues 936–1375). Upon inhibition of ASK1 by Trx its Ser967 is phosphorylated by unidentiWed kinase and this region is bound to cellular factor 143-3 that prevents TRAF-2 recruitment. Also, 14-3-3 has been reported to inhibit ASK1 activity. 14-3-3, a phosphoserine-binding molecule, binds to ASK1 speciWcally via Ser-967 of ASK1 and has been reported to inhibit ASK1-induced apoptosis. Upon dissociation from Trx homodimerized and Thr845 phosphorylated ASK1 is subjected to dephosphorylation at Ser967 that induces dissociation of 14-3-3 and mediates the recruitment of TRAF-2 protein. However, in mitochondria it is still unclear, as to which proteins from Trx-2 are involved in the inhibition of ASK1 [24–26]. There is however another mechanism for inactivation of active ASK1, which is performed by a speciWc protein phosphatase 5 (PP5), that was found to dephosphorylate Thr845 in ASK1 followed by the loss of its kinase activity [27]. ROS were found to oxidize Trx reactive thiol groups and, respectively, to mediate activation of ASK1. First, it has been discovered that hydrogen peroxide stimulation of cells leads to oxidation of Trx reactive thiol groups followed by activation of ASK1 [20]. Further studies have conWrmed that oxidative stress-induced apoptosis is mediated via ASK1 activation by the mechanism described above [1,10]. Recent studies have shown that peroxynitrite—the product of superoxide and NO condensation—can also oxidize reactive thiol groups of Trx leading to ASK1 activation [28]. Recently, glutaredoxin (GRX), a small 12 kDa protein rather similar to Trx, was found to inhibit ASK1 [29]. Epitope-tagged GRX was utilized to determine the role of GRX in oxidative stressinduced signaling and cytotoxicity in glucose-deprived human cancer cells (MCF-7/ADR and DU-145). GRXoverexpressing cells demonstrated resistance to glucose deprivation-induced cytotoxicity and decreased activation of c-Jun N-terminal kinase (JNK1). Deletion

mutants showed the C-terminal portion of ASK1 bound GRX, and glucose deprivation disrupted binding. Treatment with L-buthionine-(S,R)-sulfoximine reduced glutathione content by 99% and prevented glucose deprivation-induced dissociation of GRX from ASK1. A thiol antioxidant, N-acetyl-L-cysteine, or overexpression of an H2O2 scavenger, catalase, inhibited glucose deprivation-induced dissociation of GRX from ASK1. GRX active site cysteine residues (Cys22 and Cys25) were required for dissociation of GRX from ASK1 during glucose deprivation. In the kinase assays, it was observed that JNK and upstream kinases were regulated in an ASK1-dependent fashion during glucose deprivation. Overexpression of GRX or catalase inhibits activation of ASK1–SEK1–JNK1 signaling during glucose deprivation. These data suggested that GRX is a negative regulator of ASK1 and dissociation of GRX from ASK1 activates ASK1–SEK1–JNK1 signaling, resulting in cytotoxicity during glucose deprivation and leading to the conclusion that the GRX–ASK1 interaction is redox sensitive and regulated in a glutathione-dependent fashion by H2O2 [29]. There was obtained clear evidence that glutathione Stransferases (GSTs) also participate in regulation of MAP kinase-dependent apoptotic pathway [30–32]. GSTs are a family of Phase II detoxiWcation enzymes that catalyze the conjugation of glutathione (GSH) to a wide variety of endogenous and exogenous electrophilic compounds. Human cytosolic GSTs are highly polymorphic and can be divided into six classes:
, , , , , and . The  and  classes of GSTs play a regulatory role in the MAP kinase pathway via protein–protein interactions with JNK1 and ASK1 [30,31]. In the case of ASK1, the inhibition by GST takes place in the Trx-like manner. Dissociation of both enzymes is induced by ROS and leads to their activation [30]. For example, diallyl disulWde (DADS) treatment of neuroblastoma of SHSY5Y cells induces ROS production and consequently JNK dissociation from GST followed by its activation via phosphorylation. Moreover, treatment with JNK inhibitor I signiWcantly reduced DADS-induced apoptosis and treatment with the spin trap 5,5⬘-dimethyl-1-pyrroline N-oxide or overexpression of the antioxidant enzyme copper, zinc superoxide dismutase, resulted in the inhibition of DADS-mediated toxicity through attenuation of JNK/c-Jun pathway activation [32]. These Wndings indicate that ROS could be important on the whole way of ASK1 downstream cascade as they are involved not only in ASK1 activation but are also needed for JNK1 activation through dissociation from GST. GSTs have been implicated in the development of resistance toward chemotherapy agents. It is plausible that GSTs serve two distinct roles in the development of drug resistance via direct detoxiWcation as well as acting as an inhibitor of the MAP kinase pathway. The link between GSTs and the MAP kinase pathway provides a

V.V. Sumbayev, I.M. Yasinska / Archives of Biochemistry and Biophysics 436 (2005) 406–412

rationale as to why in many cases the drugs used to select for resistance are neither subjected to conjugation with GSH nor are they substrates for GSTs [30]. It was also found that endoplasmatic reticulum (ER) stress leads to ROS production and apoptotic cell death induced via ASK1 downstream pathway using ROS as messengers [33]. The impact of ROS on the activity of ASK1 was partly conWrmed in the studies on the rat models. Cobalt chloride mediated oxidative stress induced the activity of ASK1, which correlated with the increase in DNA fragmentation and decrease in poly-(ADP-ribose)-polymerase (PARP) activity in the rat liver in vivo. Induction of xanthine oxidase activity in the rat liver was also found to mediate an increase in the ROS that causes ASK1 activation with the increase in DNA fragmentation and decrease in PARP activity [34,35]. On the other hand, nitric oxide was reported to induce apoptosis in neurons and rat pheochromocytoma PC12 cells [28,36]. It was found that apoptosis is mediated via activation of MAP-kinase pathway. Recently, we have shown that nitric oxide can S-nitrosate Trx in human embryonic kidney (HEK293) cells, which leads to an activation of ASK1. Stimulation of HEK293 cells with S-nitrosoglutathione (GSNO) for 2, 4, 8, and 16 h also caused Trx S-nitrosation, which showed straight correlation with ASK1 activation based on Western blot detection of the enzyme, immunoprecipitation assay, and measurement of its catalytic activity. These results suggest that S-nitrosation of Trx induces ASK1 activation. Treatment of cells with N-acetyl-cysteine for 2 h after 8 h of pretreatment with GSNO caused an increase in glutathione and nulliWed ASK1 activation. On the other hand, ASK1 is inhibited by S-nitrosation of its Cys869 residue. In our studies, we have observed the activation of ASK1 in HEK293 cells upon stimulation with NO-donors [37–39]. The formation of reactive intermediates derived from oxygen and NO has been invoked in mechanisms for degradation of biomacromolecules with accompanying pathophysiological consequences. Appearance of superoxide and NO in equal concentrations leads to peroxynitrite formation, however peroxynitrite actions are abolished by 2- to 3-fold excess of NO resulted in further pre-formation of peroxynitrite into N2O3-like species, which nitrosate protein thiol groups. We have also observed S-nitrosation of reactive Trx thiol groups in nitric oxide/superoxide system. It was found that Trx thiol groups are the targets for S-nitrosation by N2O3-like species generated in the system containing xanthine/xanthine oxidase (superoxide producing system) and DEA/NO—the *NO donating compound, however, they have shown low sensitivity to the NO-radical derived from DEA/NO. N2O3-dependent S-nitrosation of Trx at approximately 2-fold of NO excess compared to the superoxide amount resulting in dissociation and activation of ASK1. However, approxi-

409

mately 4-fold of NO excess compared to a superoxide production preserved the level of dissociated ASK1 but decreased its activity due to S-nitrosation of the enzyme more likely in the position of Cys869 [37–39]. Other Wndings have suggested that Cys69 of Trx is a potential target for S-nitrosation, however, this posttranslational modiWcation has an anti-apoptotic impact in endothelial cells. These Wndings were supported by another group, who found the same eVect in the cardiovascular system by using cell culture assays and animal models. Those data also reXect the situation in the cardiovascular system and do not provide any evidence about other cell types [40,41]. Taken together, the data reporting pro- and anti-apoptotic impact of Trx S-nitrosation suggest a cell type speciWc Trx reactivity to the NO-dependent modiWcations of thiol groups. We have also found that at least two SH-groups of pure human Trx are sensitive to nitrosation, while other authors have reported that there are more than 10. However, there is a reason to believe that this amount is the combination of nitrosated thiol groups and some unspeciWc interactions as human Trx has less than 10 thiol groups [41]. In this respect, we could say that in neurons and HEK293 cells S-nitrosation of Trx has an apoptotic impact, however, in cardiovascular system it protects cells from the programmed death. Other data suggest hypoxia inducible factor 1
(HIF1
) to participate in p53 stabilization, which takes place upon ASK1 activation, and is essential for programmed cell death [42–44]. HIF-1 is a heterodimeric transcription factor composed of
and  subunits. While HIF-1 is constitutively expressed in many cell types, HIF-1
is present at low or undetectable amounts under normal oxygen supply because the protein is rapidly degraded by the ubiquitin–proteasome system. HIF-1
protein is a master regulator to sense decreased oxygen partial pressure that initiates a complex biological response, which determines cell adaptation to patho-physiological situations of decreased oxygen availability. Recently, nitric oxide has emerged as a messenger with the ability to stabilize HIF-1
and to transactivate HIF-1 under normoxia [45– 48]. Considering that RNS are recognized for post-translation protein modiWcations, among others S-nitrosation, we investigated whether HIF-1
is a target for Snitrosation. We have found that in vitro NO+ donating NO donors such as GSNO and S-nitroso-N-acetyl-penicillamine (SNAP) provoked massive S-nitrosation of puriWed HIF-1
. All 15 free thiol groups found in human HIF-1
are subjected to S-nitrosation. Thiol modiWcation is not shared by spermine-NONOate, a NO radical donating compound. However, spermine-NONOate in the presence of superoxide, generated by xanthine/xanthine oxidase, regained S-nitrosation, most likely via formation of a N2O3-like species. In vitro, S-nitrosation of HIF-1
was attenuated by the addition of GSH or

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ascorbate. In renal carcinoma cells (RCC4) lacking the von Hippel–Lindau protein, which is found to be physiological inhibitor of HIF-1
as well as in HEK293 cells GSNO or SNAP reproduced S-nitrosation of HIF-1
, however, with a signiWcantly reduced potency that amounted to modiWcation of three to four thiols, only. Importantly, endogenous formation of NO in RCC4 cells via inducible NO synthase elicited S-nitrosation of HIF-1
that was sensitive to inhibition of inducible NO synthase activity with N-monomethyl-L-arginine. NO-stabilized HIF-1
was susceptible to the addition of N-acetyl-cysteine that destabilized HIF-1
in close correlation to the disappearance of S-nitrosated HIF-1
. In conclusion, HIF-1
is a target for S-nitrosation by exogenously and endogenously produced NO [49,50]. Stable HIF-1
protein was found to interact with p53 complexed protein mdm2. Upon normal physiological conditions JNK binds p53 between its 97th and 116th amino acid residues mediating its ubiquitination and proteasomal degradation [14,15]. Phosphorylated JNK loses its aYnity to p53, which results in p53 release. Free p53 is subjected to interaction with mdm2 that can induce protein degradation. Recruitment of HIF-1
pro-

tein by mdm2 complexed to p53 turns the process into an opposite eVect resulting in p53 stabilization making it capable of inducing programmed cell death [42–44]. The data outlined give an opportunity to suggest a possible participation of HIF-1
protein in apoptotic cell death induced by nitric oxide via MAP kinasedependent pathway, which means that stabilized and S-nitrosated HIF-1
protein is necessary for stabilization of p53 released upon activation of ASK1 downstream pathway. The general scheme reXecting the possible mechanisms of MAP-kinase-dependent apoptotic cell death mediated by ROS and nitric oxide is shown in Fig. 2. Recent studies suggest that oxidized low density lipoprotein (oxLDL) formed upon atherosclerosis induces the apoptotic cell death in macrophages via p53 pathway [51]. This kind of apoptosis is mediated by ROS formed upon oxLDL impact [51]. One can hypothesize that oxLDL induces apoptosis by p53 stabilization supported by the ROS-dependent ASK1 activation. On the other hand, recently there was obtained evidence that oxLDL induced hypoxia-inducible HIF-1
protein accumulation in human macrophages (Mono-Mac-6) under

Fig. 2. Possible mechanisms of MAP-kinase-dependent apoptotic cell death mediated by ROS and RNS.

V.V. Sumbayev, I.M. Yasinska / Archives of Biochemistry and Biophysics 436 (2005) 406–412

normoxia [52]. HIF-1
accumulation was attenuated by pre-treatment with the antioxidant N-acetyl-L-cysteine, the nitric oxide (NO) donor S-nitrosoglutathione (GSNO), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors such as diphenyleniodonium (DPI) or 4-(2-aminoethyl)-benzenesulfonyl Xuoride (AEBSF), thus implicating the contribution of oxLDL-generated ROS. Whereas oxLDL did not modulate HIF-1
mRNA levels, experiments with cycloheximide pointed to a translational mechanism in oxLDL action. HIF-1-dependent luciferase reporter gene analysis underscored HIF-1 transactivation. These results indicate that oxLDL induced HIF-1
accumulation and HIF-1-dependent reporter gene activation in human macrophages via a redox-mediated pathway [52]. Based on those data one can assume that HIF-1
protein is needed to stabilize p53 complexed to mdm2 as the concentrations used were found to induce the apoptotic death of Mono-Mac-6 macrophages [51,52].

Other recently described mechanisms of ASK1 regulation Recent studies suggest that ROS/RNS are not the only messengers responsible for transduction of signals for ASK1 activation. Several mechanisms, which do not assume direct implication of ROS/RNS in activation of ASK1, were described. Currently, a novel mechanism of ASK1-mediated cell death that is triggered by the interaction with Daxx protein was discovered. Co-transfection of ASK1 and Daxx induced a caspase-independent cell-death process characterized at the morphological level by distinctive crumpled nuclei easily distinguishable from the condensed and fragmented nuclei seen during classical caspase-dependent apoptosis. The kinase activity of ASK1 was not involved in this process, because mutants lacking kinase activity were as eYcient as wild type ASK1 in mediating Daxx-induced cell death. ASK1N, a deletant that lacks the C-terminal half including the kinase domain of ASK1, was constitutively active in producing crumpled nuclei. In contrast, ASK1_N, the reciprocal deletant that possesses constitutive kinase activity, produced fragmented nuclei typical of caspase-dependent death processes. It has become evident that ASK1 could also possess a caspase-independent killing function that is independent of its kinase activity and is activable by interaction with Daxx. In the physiological situation, such an activity is induced as a consequence of the translocation of Daxx from the nucleus to the cytoplasm, a condition that occurs following activation of the death receptor Fas [53]. Fas activation was found to induce Daxx to interact with ASK1, which consequently relieved an inhibitory intramolecular interaction between the amino- and carboxyl-termini of ASK1, activating its kinase activity. The Daxx–ASK1 connection completes a signaling

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pathway from a cell surface death receptor to kinase cascades that modulate nuclear transcription factors [54]. Apoptosis linked gene-2 (ALG-2) is an essential protein for the execution of apoptosis whose function is largely unknown. It was recently demonstrated that ALG-2 could interact with the C-terminus of the ASK1 in BOSC23 cells as well as in vitro. ASK1 failed to bind to an isotype of ALG-2 found in the liver, ALG-2,1, in which two amino acids (Gly-121 and Phe-122) are deleted. This implied that the interaction is very speciWc. Co-transfection with ALG-2 resulted in the nuclear presence of ASK1 and inhibited the activation of JNK by ASK1 in BOSC23 cells. This study reported that ALG-2 could regulate the subcellular localization and the JNK activity modulation of ASK1 by direct interaction [55]. The most recent studies reported the availability of estrogen responsive element (ERE) in the ASK1 inhibiting PP5 promoter region in lung carcinoma, hepatoma, and breast carcinoma cells [56]. The Wnding suggests the possibility of apoptosis inhibition in carcinoma cells by estrogens and estrogen-like environmental endocrine disruptors [56,57]. Taken together, the data discussed in this paper as well as the reports, which we did not include in the present review suggest that ROS and RNS are critical messengers participating in the regulation of MAP-kinase-dependent apoptotic pathway by diVerent signaling systems. A couple of ROS- or RNS-independent signaling mechanisms involved in the ASK1 downstream MAP kinase pathway were also described. However, one cannot rule out that these mechanisms could also interfere with ROS/RNS production, and this is an interesting and important subject for further studies.

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