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PERSPECTIVES IN PHARMACOLOGY

A Death-Promoting Role for Extracellular Signal-Regulated Kinase

Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina

Received May 6, 2006; accepted June 23, 2006.

	Abstract

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Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), which are members of the mitogen-activated protein kinase superfamily, have been well characterized and are known to be involved in cell survival; however, recent evidence suggests that the activation of ERK1/2 also contributes to cell death in some cell types and organs under certain conditions. For example, ERK1/2 is activated in neuronal and renal epithelial cells upon exposure to oxidative stress and toxicants and deprivation of growth factors, and inhibition of the ERK pathway blocks apoptosis. ERK activation also occurs in animal models of ischemia- and trauma-induced brain injury and cisplatin-induced renal injury, and inactivation of ERK reduces the extent of tissue damage. In some studies, ERK has been implicated in apoptotic events upstream of mitochondrial cytochrome c release, whereas other studies have suggested the converse that ERK acts downstream of mitochondrial events and upstream of caspase-3 activation. ERK also can contribute to cell death through the suppression of the antiapoptotic signaling molecule Akt. Here we summarize the evidence and mechanism of ERK-induced apoptosis in both cell culture and in animal models.

	General Cascades of Cell Death

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Extensive studies to elucidate the mechanisms by which apoptosis is induced and transduced have resulted in the generally accepted theory that intrinsic and extrinsic mechanisms are involved (Fig. 1) (Fadeel and Orrenius, 2005; Kim et al., 2006). Intrinsic pathways are activated by specific stress stimuli and lead to mitochondrial cytochrome c release, the activation of caspase-9 through Apaf-1, and the activation of executioner caspases (e.g., caspase-3) (Fadeel and Orrenius, 2005). The extrinsic apoptotic pathway is initiated by the activation of death receptors, such as the TNF- receptor and Fas, and caspase-8 (Kim et al., 2006). Activated caspase-8 can directly activate executioner caspases and/or induce cleavage of Bid to truncated Bid. Truncated Bid is translocated to the mitochondria, prompting cytochrome c release and subsequent activation of caspase-3 (Li et al., 1998; Runden et al., 1998).

View larger version (63K): [in this window] [in a new window]   Fig. 1. Mechanisms of ERK-mediated apoptosis. ERK may regulate apoptosis and cell survival at multiple points that include increasing p53 and BAX action, increasing caspase-3 and caspase-8 activities, decreasing Akt activity, and increasing TNF- production.

ERK Signaling Pathway
ERK belongs to a family of mitogen-activated protein kinases (MAPKs) that comprises ERKs, c-Jun N-terminal kinase/stress-activated protein kinases, and p38 kinases. Within the ERK group, there are eight isoforms (i.e., ERK1, 2, 3, 4, 5, 6, 7, and 8) (Bogoyevitch and Court, 2004; Yoon and Seger, 2006) of which ERK1 and ERK2 have been extensively studied. ERK1 and ERK2 are regulated by the dual-specificity kinases MEK1 and MEK2 through phosphorylation at both a threonine and an adjacent tyrosine residue within a dual-specificity motif (Thr-Glu-Tyr). MEK1 and MEK2 can be activated by multiple MAPK kinase kinases, although Raf kinase family members typically serve as dedicated MEK1/2 activators (Garrington and Johnson, 1999). Low molecular weight G-proteins (Ras, Rac, Rho, Cdc42, etc.), each associated with growth factor receptor activation and cellular adhesion, can contribute to Raf activation either directly or indirectly (Peyssonnaux and Eychene, 2001).

ERK1/2 also is activated in response to various stress stimuli through divergent mechanisms involving the Ras-Raf-MEK pathway (Strniskova et al., 2002; Kyosseva, 2004; Roux and Blenis, 2004; Baines and Molkentin, 2005; Rennefahrt et al., 2005). Depending upon the cell type, the stimulus, and the duration of activation, a variety of biological responses (i.e., cell proliferation, migration, differentiation, and apoptosis) are associated with ERK activation (Strniskova et al., 2002; Kyosseva, 2004; Roux and Blenis, 2004; Baines and Molkentin, 2005; Rennefahrt et al., 2005). This proapoptotic perspective of ERK will comprise the remainder of this review.

ERK Signaling Mediates Apoptosis in Cultured Cells
Bhat and Zhang (1999) first reported that inhibition of ERK using the MEK1 inhibitor PD98059 (2'-amino-3'-methoxyflavone) rescues oligodendrocytes from H₂O₂-induced cell death, and this observation was subsequently confirmed in HeLa cells (Wang et al., 2000), cortical neurons (Lesuisse and Martin, 2002), and primary -cells (Pavlovic et al., 2000) (Table 1). In renal cell lines (LLC-PK1 and OK) and primary cultures of renal proximal tubular cells, inhibition of ERK improved cell survival by inhibiting apoptosis after cisplatin exposure (Ishikawa and Kitamura, 2000; Nowak, 2002; Kim et al., 2005). The proapoptotic role of ERK in renal epithelial cells is not limited to cisplatin exposure; ERK activation is also associated with cell death induced by reactive oxygen species (ROS) (Tikoo et al., 2001; Ramachandiran et al., 2002; Dong et al., 2004), Escherichia coli toxins (Chen et al., 2004), zinc (Matsunaga et al., 2005), and cephaloridine (Kohda et al., 2003). ERK activation also has been implicated in cell death induced by deprivation of survival factors. For example, withdrawal of survival factors from mouse kidney proximal tubular epithelial cells led to a progressive increase in ERK1/2 activity, and inhibition of ERK1/2 maintained cell survival (Sinha et al., 2004). Finally, ERK1/2 activation is involved in doxorubicin-induced apoptosis in human hepatoma cell lines (HepG2 and Huh-7) (Alexia et al., 2004), amyloid-induced neurotoxicity in primary hippocampal neurons (Medina et al., 2005), and CD40-mediated apoptosis in cholangiocytes (Ahmed-Choudhury et al., 2006).

Most of the above-mentioned studies addressed the role of ERK in apoptosis using MEK inhibitor PD98059 or U0126 (1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene) (Alessi et al., 1995; Favata et al., 1998). Recently, Kim et al. (2005) used molecular approaches to examine the role of the ERK pathway in cell death of renal epithelial cells. They found that transient transfection of constitutively active MEK1 increased H₂O₂-induced apoptosis, whereas the dominant-negative mutant of MEK1 led to an inhibition of H₂O₂-mediated cell death.. Likewise, Goillot et al. (1997) demonstrated that interference with the ERK pathway by expression of dominant-negative MEK1 resulted in inhibition of Fas-mediated apoptosis. These in vitro studies support a significant role for ERK in mediating apoptosis.

ERK Signaling Mediates Injury-Induced Tissue Damage in Vivo
ERK-mediated cell death also has been reported in numerous animal models. In a mouse model of stroke induced by transient occlusion of the middle cerebral artery, an increase in phosphorylated ERK in the nuclei of cortical cells was detected and pretreatment with PD98059 blocked ERK phosphorylation, resulting in a 55% decrease in focal infarct volume at 22 h and a 36% decrease at 72 h (Alessandrini et al., 1999). Using the same model, researchers confirmed these results using two additional MEK1 inhibitors U0126 and SL327 (Namura et al., 2001; Wang et al., 2003, 2004b). In a gerbil model of forebrain ischemia induced by bilateral carotid artery occlusion, Namura et al. (2001) obtained similar results with MEK1 inhibitors. ERK also was rapidly activated in damaged tissue in a controlled cortical-impact model of traumatic injury in mice, and ERK pathway inhibition with PD98059 prior to trauma resulted in a significant reduction of cortical lesion volumes 7 days after trauma (Mori et al., 2002; Clausen et al., 2004), Confocal immunohistochemistry showed that phospho-ERK colocalized with the neuronal nuclei marker Neu-N in the injured brain (Fig. 1).

However, increased phospho-ERK1/2 staining was also detected in neurons that survived ischemic injury in a rat and mouse model of focal cerebral ischemia (Irving et al., 2000; Namura et al., 2001), suggesting that ERK1/2 activation may mediate cell survival in these areas. In support of an anti-apoptotic role of ERK, Gonzalez-Zulueta et al. (2000) reported that activation of the Ras/ERK cascade was critical for the development of ischemic tolerance in cortical neurons. Finally, inhibition of ERK1/2 with PD98059 failed to protect gerbils against ischemic cell death in the hippocampal CA1 region (Sugino et al., 2000) and did not block cerebral endothelial cell death after hypoxia reoxygenation (Lee and Lo, 2003). These differences in the outcome of ERK activation may be attributed to the differences in the experimental models.

In a mouse model of cisplatin-induced nephrotoxicity, Jo et al. (2005) observed that ERK1/2 phosphorylation increased mainly in distal tubules and collecting ducts 24 h after cisplatin administration and persisted until 72 h. Inhibition of ERK phosphorylation by U0126 pretreatment reduced tissue damage and improved renal function. A crucial role of ERK activation in mediating renal cell injury also was observed in rat renal cortical slices treated with cephaloridine, a cephalosporin antibiotic (Kohda et al., 2003). Furthermore, serum thymic factor attenuated cisplatin nephrotoxicity by suppressing cisplatin-induced ERK activation (Kohda et al., 2005). These studies, coupled with the in vitro studies, reveal that ERK is a critical mediator in nephrotoxicity. Although ERK is activated after renal ischemia/reperfusion injury in animals (Park et al., 2001), the role of ERK in ischemia/reperfusion-induced renal injury remains to be established.

	Mechanisms of ERK-Induced Apoptosis

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ERK-Mediated Regulation of the Intrinsic Pathway
Because the intrinsic pathway is characterized by mitochondrial outer membrane permeabilization, cytochrome c release, and caspase activation, the association of ERK with these events has been investigated in vivo and in vitro. In vivo studies revealed that ERK1/2 acts upstream of caspase-3 in cisplatin-induced cell death in the kidney (Jo et al., 2005) and in the brain after ischemia/reperfusion (Wang et al., 2003). Using HeLa cells, Wang et al. (2000) showed that ERK1/2 inhibition blocks cytochrome c release and subsequent activation of caspase-3 in cisplatin-induced apoptosis. In a renal cell line (OK cells), Kim et al. (2005) reported that ERK activation is required for mitochondrial membrane depolarization, cytochrome c release, and caspase-3 activation after cisplatin exposure. Nowak (2002) reported that phosphorylated ERK1/2 was detected in mitochondria and associated with loss of mitochondrial function in cisplatin-treated primary cultures of renal proximal tubular cells. However, ERK inhibition blocked caspase-3 activation without affecting cytochrome c release from mitochondria (Nowak, 2002). Thus, ERK1/2 may act on mitochondria to cause cytochrome c release and/or may regulate activation of caspase-3 downstream of cytochrome c release (Fig. 1).

ERK may act on mitochondria through Bax and/or p53. Bax is a member of the Bcl-2 family of proteins and acts as proapoptotic molecule. During apoptosis induced by a variety of stimuli, Bax is translocated to the mitochondria, where it promotes the release of proapoptotic proteins from the intermembrane space (Degli Esposti and Dive, 2003). In renal epithelial and osteoblastic cells, Bax expression is increased after cisplatin or H₂O₂, and inhibition of the ERK pathway decreased Bax expression (Kim et al., 2005; Park et al., 2005). Similar to the role of ERK in the regulation of Bax expression, ERK activation is also associated with up-regulation of p53 expression in HeLa cells treated with shikonin (a red naphthoquinone pigment isolated from the ground rhizome of lithospermum erythrorhizon) (Wu et al., 2005) and in lens epithelial cells treated with calcimycin, a calcium mobilizer (Li et al., 2005). In the presence of apoptotic stimuli, p53 has been reported to translocate to the mitochondria to inhibit the action of the antiapoptotic Bcl-x through the formation of a p53/Bcl-x complex (Petros et al., 2004) or to directly promote the proapoptotic activities of Bak (Mihara et al., 2003; Leu et al., 2004). Inhibition of Bcl-x and induction of Bax activity leads to cytochrome c release and caspase activation (Moll et al., 2005). In addition, ERK may regulate apoptosis via direct phosphorylation of p53. ERK can induce p53 phosphorylation at serine residue 15 (Persons et al., 2000), and inactivation of ERK resulted in p53 dephosphorylation and inhibited apoptosis (Brown and Benchimol, 2006). Together, these data suggest that Bax and p53 are important components in the ERK-mediated apoptotic signaling pathways (Fig. 1).

ERK-Mediated Regulation of the Extrinsic Pathway
ERK may induce apoptosis through regulation of the extrinsic apoptotic pathway. Jo et al. (2005) examined the effect of ERK inhibition on TNF- expression and subsequent caspase-3 activation in cisplatin-induced acute renal failure in mice. They found that inhibiting ERK1/2 reduced TNF- expression, caspase-3 activation, and apoptosis in kidney tissue, suggesting that ERK1/2 pathway may also participate in apoptosis by increasing an upstream signal for TNF- production. It is established that increases in interleukin 1 (IL-1) are closely associated with brain injury after cerebral ischemia (Barone and Feuerstein, 1999; Emsley and Tyrrell, 2002). Recently, Wang et al. (2004a) showed that cerebral ischemia in mice induces ERK activation and IL-1 expression, and inhibition of ERK activation by U0126 prevented increases in IL-1 mRNA. These studies implicate ERK-mediated expression of death ligands and proinflammatory cytokines as an important mechanism in exacerbating tissue injury (Fig. 1).

The extrinsic apoptotic pathway relies on the activation of an initial caspase, caspase-8. Cagnol et al. (2006) examined the effect of ERK pathway activation on caspase-8 and apoptosis in human embryonic kidney 293 cells that express an inducible form of Raf-1. They showed that prolonged ERK stimulation activated caspase-8 and potentiated Fas signaling and apoptosis, whereas expression of Bcl-X_L, an inhibitor of apoptosis, did not significantly alter the apoptotic rate (Cagnol et al., 2006). These data suggest that ERK can regulate the apoptotic pathway at the level of caspase-8 (Fig. 1).

ERK-Mediated Suppression of Survival Signaling
Promotion of cell death by ERK activation also may result from the suppression of survival signaling pathways. The phosphatidylinositol 3-kinase/Akt pathway plays a critical role in the regulation of cell survival, and most growth and survival factors activate this pathway (Amaravadi and Thompson, 2005). Recently, it was reported that withdrawal of soluble survival factors from primary cultures of mouse renal proximal tubular cells led to ERK1/2 activation that was accompanied by a gradual decrease in Akt activity and apoptosis (Sinha et al., 2004). Inhibition of ERK1/2 with U0126 or PD98059 in the cells deprived of survival factors not only prevented the decline in Akt activity but also resulted in cell survival (Sinha et al., 2004). These results support the idea that ERK1/2 activation in response to survival factor deprivation contributed to cell death via the suppression of the Akt pathway (Fig. 1). Although the precise mechanism by which ERK1/2 inhibits Akt remains unclear, ERK1/2 and Akt have been reported to coexist in a multimolecular complex containing at least ERK1/2, Akt, ribosomal S6 kinase 1, and phosphoinositide-dependent kinase 1 (Sinha et al., 2004). Whether ERK suppresses Akt activity through regulation of ribosomal S6 kinase 1 and phosphoinositide-dependent kinase 1 or through other signaling molecules requires further investigation.

Upstream Inducers of ERK in Apoptosis
ERK activation can be induced by different stimuli via distinct mechanisms. For example, Arany et al. (2004) reported that the EGF receptor mediates ERK activation, and inhibition of the EGF receptor blocked cisplatin-induced ERK activation and apoptosis in mouse renal proximal tubules. Likewise, Lee et al. (2005) showed that H₂O₂ triggers EGF receptor activation and that EGF receptor inactivation attenuated apoptosis in OK cells. Consequently, the death signal may initiate at a cellular membrane receptor and then propagate through an ERK-mediated signaling pathway.

Ras and Raf are downstream of growth factor receptors and mediate activation of MEK-ERK (Magnuson et al., 1994; Downward, 1998). Li et al. (2005) demonstrated that calcimycin-induced apoptosis of lens epithelial cells is mediated by MEK and ERK through a Ras and Raf-dependent pathway. Woessmann et al. (2002) showed that Ras-mediated activation of ERK by cisplatin induces cell death in osteosarcoma and neuroblastoma cell lines. In addition, calcium can induce ERK and apoptosis through a Ras-dependent and Raf-independent mechanism (Vossler et al., 1997; Li et al., 2005). Src also can transduce EGF receptor activation to ERK in cisplatin-induced apoptosis of mouse proximal tubular cells (Arany et al., 2004). In contrast, Sinha et al. (2004) reported that growth factor depletion-mediated cell death is dependent on ERK but not Raf. These data suggest that divergent intermediates are involved in transducing the death signal from the cellular membrane to ERK.

ROS play an important role in regulating cellular events, leading to ERK activation and subsequent apoptosis. In addition to exogenous ROS activation of ERK and apoptosis, cellular production of ROS—due to a stimulus—can result in ERK activation. For example, cisplatin-induced cytotoxicity is closely related to increased generation of ROS (Sasada et al., 1996; Miyajima et al., 1997). ERK activation prompted by asbestos or the deprivation of growth factors can be blocked by the addition of ROS scavengers. Furthermore, H₂O₂ generation and ERK activation are involved in 2,3,5-tris(glutathion-S-yl)hydroquinone-induced cell death in LLC-PK1 cells (Tikoo et al., 2001; Ramachandiran et al., 2002; Dong et al., 2004). These studies suggest that ROS produce a specific environment that results in ERK-induced cell death.

The Role of ERK5 in Apoptosis
Studies examining the role of ERK in cell death have primarily relied upon MEK1 inhibitors U0126 and PD98059. Recently, it was reported that biological actions previously attributed to ERK1/2 may, in fact, be mediated by ERK5, a newer member of the MAPK family, because PD98059 and U0126 inhibit MEK1/2 as well as MEK5 (Kamakura et al., 1999; Cavanaugh et al., 2001). ERK5, also called big MAPK 1 or BMK1, contains a dual-phosphorylation motif (Thr-Glu-Tyr) similar to that in ERK1/2, and the N-terminal half of ERK5 shares sequence homology with other members of the MAPK family. However, a large C terminus and a unique loop-12 sequence distinguish it from ERK1/2. ERK5 is phosphorylated and activated by MEK5 but not by MEK1 or MEK2 (English et al., 1995; Zhou et al., 1995).

Similar to ERK1/2, activation of ERK5 plays a role in cell survival in response to a variety of stimuli, including oxidants and toxicants (Suzaki et al., 2002; Pi et al., 2004). Recently, ERK5 activation has been shown to promote apoptosis. For example, Sturla et al. (2005) reported that overexpression of ERK5 increased apoptosis in two medulloblastoma cell lines and primary cultures of patched heterozygous mouse medulloblastomas upon exposure to neurotrophin-3, whereas expression of small interfering RNA for the ERK5 activator, MEK5, inhibited neuotrophin-3-induced apoptosis. Furthermore, inhibition of myocyte enhancer factor 2, a specific target of ERK5, by a dominant-negative mutant of myocyte enhancer factor 2 blocked MEK5/ERK5-induced cell death (Sturla et al., 2005). Although ERK5 has an apparent role in cell death, the mechanisms for this are unclear. Because many stimuli that induce ERK1/2 activation also activate ERK5, it is tempting to speculate that the ERK5 pathway may also be involved in the death of other cell types.

	Conclusions and Future Directions

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Although ERK has generally been considered a survival signaling pathway, clear evidence exists that the ERK pathway mediates apoptosis induced by different stimuli in different tissues. The mechanisms by which ERK mediates apoptosis remain poorly understood and may occur at different levels. ERK1/2 may act upstream of mitochondrial cytochrome c release and caspase-3 activation through up-regulation of Bax and p53 and through suppression of Akt-mediated survival signaling. Further studies are necessary to elucidate the activated signal transduction upstream and downstream of the cascades and to define the cross-talk among the cascades and other signaling pathways.

The rationale for a signaling pathway being responsible for cell survival and apoptosis is not clear. At present, the signaling of survival or apoptosis by ERK seems to be dependent on the model system and injury paradigm. Furthermore, the kinetics and duration of ERK activation may play an important role in influencing its effect on cell fate. It has been reported that prolonged ERK activation is accompanied by the proapoptotic effect of ERK (di Mari et al., 1999), whereas a transient activation of ERK protects cells from death (Arany et al., 2004). Nevertheless, the protective effect of ERK inhibition has been reported in animal models of ischemia/reperfusion, and ERK activation was reported in humans who had experienced a stroke (Slevin et al., 2000); thus, the protection strategies that target these mechanisms merit further exploration.

	Footnotes

 
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

doi:10.1124/jpet.106.107367.

ABBREVIATIONS: TNF-, tumor necrosis factor-; ERK, extracellular signal-regulated protein kinase(s); MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase; PD98059, 2'-amino-3'-methoxyflavone; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)-butadiene; ROS, reactive oxygen species; IL, interleukin; EGF, epidermal growth factor; SL327, Z and E--(amino-((4-aminophenyl)thio)methylene-2-(trifluoromethyl)benzeneacetonitrile.

Address correspondence to: Dr. Rick G. Schnellmann, Department of Pharmaceutical Sciences, Medical University of South Carolina, 280 Calhoun St., P. O. Box 250140, Charleston, SC 29425. E-mail: schnell{at}musc.edu

	References

Top Abstract General Cascades of Cell... Mechanisms of ERK-Induced... Conclusions and Future... References

 

Ahmed-Choudhury J, Williams KT, Young LS, Adams DH, and Afford SC (2006) CD40 mediated human cholangiocyte apoptosis requires JAK2 dependent activation of STAT3 in addition to activation of JNK1/2 and ERK1/2. Cell Signal 18: 456–468.[CrossRef][Medline]

Alessandrini A, Namura S, Moskowitz MA, and Bonventre JV (1999) MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. Proc Natl Acad Sci USA 96: 12866–12869.[Abstract/Free Full Text]

Alessi DR, Cuenda A, Cohen P, Dudley DT, and Saltiel AR (1995) PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem 270: 27489–27494.[Abstract/Free Full Text]

Alexia C, Fallot G, Lasfer M, Schweizer-Groyer G, and Groyer A (2004) An evaluation of the role of insulin-like growth factors (IGF) and of type-I IGF receptor signalling in hepatocarcinogenesis and in the resistance of hepatocarcinoma cells against drug-induced apoptosis. Biochem Pharmacol 68: 1003–1015.[CrossRef][Medline]

Amaravadi R and Thompson CB (2005) The survival kinases Akt and Pim as potential pharmacological targets. J Clin Investig 115: 2618–2624.[CrossRef][Medline]

Arany I, Megyesi JK, Kaneto H, Price PM, and Safirstein RL (2004) Cisplatin-induced cell death is EGFR/src/ERK signaling dependent in mouse proximal tubule cells. Am J Physiol 287: F543–F549.

Baines CP and Molkentin JD (2005) STRESS signaling pathways that modulate cardiac myocyte apoptosis. J Mol Cell Cardiol 38: 47–62.[CrossRef][Medline]

Barone FC and Feuerstein GZ (1999) Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab 19: 819–834.[Medline]

Bhat NR and Zhang P (1999) Hydrogen peroxide activation of multiple mitogen-activated protein kinases in an oligodendrocyte cell line: role of extracellular signal-regulated kinase in hydrogen peroxide-induced cell death. J Neurochem 72: 112–119.[CrossRef][Medline]

Boatright KM and Salvesen GS (2003) Mechanisms of caspase activation. Curr Opin Cell Biol 15: 725–731.[CrossRef][Medline]

Bogoyevitch MA and Court NW (2004) Counting on mitogen-activated protein kinases–ERKs 3, 4, 5, 6, 7 and 8. Cell Signal 16: 1345–1354.[CrossRef][Medline]

Brown L and Benchimol S (2006) The involvement of MAPK signaling pathways in determining the cellular response to p53 activation: cell cycle arrest or apoptosis. J Biol Chem 281: 3832–3840.[Abstract/Free Full Text]

Cagnol S, Van Obberghen-Schilling E, and Chambard JC (2006) Prolonged activation of ERK1,2 induces FADD-independent caspase 8 activation and cell death. Apoptosis 11: 337–346.[CrossRef][Medline]

Cavanaugh JE, Ham J, Hetman M, Poser S, Yan C, and Xia Z (2001) Differential regulation of mitogen-activated protein kinases ERK1/2 and ERK5 by neurotrophins, neuronal activity, and cAMP in neurons. J Neurosci 21: 434–443.[Abstract/Free Full Text]

Chen J, Liu X, Mandel LJ, and Schnellmann RG (2001) Progressive disruption of the plasma membrane during renal proximal tubule cellular injury. Toxicol Appl Pharmacol 171: 1–11.[CrossRef][Medline]

Chen M, Bao W, Aizman R, Huang P, Aspevall O, Gustafsson LE, Ceccatelli S, and Celsi G (2004) Activation of extracellular signal-regulated kinase mediates apoptosis induced by uropathogenic Escherichia coli toxins via nitric oxide synthase: protective role of heme oxygenase-1. J Infect Dis 190: 127–135.[CrossRef][Medline]

Clausen F, Lundqvist H, Ekmark S, Lewen A, Ebendal T, and Hillered L (2004) Oxygen free radical-dependent activation of extracellular signal-regulated kinase mediates apoptosis-like cell death after traumatic brain injury. J Neurotrauma 21: 1168–1182.[CrossRef][Medline]

Columbano A (1995) Cell death: current difficulties in discriminating apoptosis from necrosis in the context of pathological processes in vivo. J Cell Biochem 58: 181–190.[CrossRef][Medline]

de Bernardo S, Canals S, Casarejos MJ, Solano RM, Menendez J, and Mena MA (2004) Role of extracellular signal-regulated protein kinase in neuronal cell death induced by glutathione depletion in neuron/glia mesencephalic cultures. J Neurochem 91: 667–682.[CrossRef][Medline]

Degli Esposti M and Dive C (2003) Mitochondrial membrane permeabilisation by Bax/Bak. Biochem Biophys Res Commun 304: 455–461.[CrossRef][Medline]

di Mari JF, Davis R, and Safirstein RL (1999) MAPK activation determines renal epithelial cell survival during oxidative injury. Am J Physiol 277: F195–F203.[Medline]

Dong J, Ramachandiran S, Tikoo K, Jia Z, Lau SS, and Monks TJ (2004) EGFR-independent activation of p38 MAPK and EGFR-dependent activation of ERK1/2 are required for ROS-induced renal cell death. Am J Physiol 287: F1049–F1058.

Downward J (1998) Ras signalling and apoptosis. Curr Opin Genet Dev 8: 49–54.[CrossRef][Medline]

Emsley HC and Tyrrell PJ (2002) Inflammation and infection in clinical stroke. J Cereb Blood Flow Metab 22: 1399–1419.[CrossRef][Medline]

English JM, Vanderbilt CA, Xu S, Marcus S, and Cobb MH (1995) Isolation of MEK5 and differential expression of alternatively spliced forms. J Biol Chem 270: 28897–28902.[Abstract/Free Full Text]

Fadeel B and Orrenius S (2005) Apoptosis: a basic biological phenomenon with wide-ranging implications in human disease. J Intern Med 258: 479–517.[CrossRef][Medline]

Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, Van Dyk DE, Pitts WJ, Earl RA, Hobbs F, et al. (1998) Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 273: 18623–18632.[Abstract/Free Full Text]

Garrington TP and Johnson GL (1999) Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr Opin Cell Biol 11: 211–218.[CrossRef][Medline]

Goillot E, Raingeaud J, Ranger A, Tepper RI, Davis RJ, Harlow E, and Sanchez I (1997) Mitogen-activated protein kinase-mediated Fas apoptotic signaling pathway. Proc Natl Acad Sci USA 94: 3302–3307.[Abstract/Free Full Text]

Gomez-Santos C, Ferrer I, Reiriz J, Vinals F, Barrachina M, and Ambrosio S (2002) MPP+ increases alpha-synuclein expression and ERK/MAP-kinase phosphorylation in human neuroblastoma SH-SY5Y cells. Brain Res 935: 32–39.[CrossRef][Medline]

Gonzalez-Zulueta M, Feldman AB, Klesse LJ, Kalb RG, Dillman JF, Parada LF, Dawson TM, and Dawson VL (2000) Requirement for nitric oxide activation of p21^ras/extracellular regulated kinase in neuronal ischemic preconditioning. Proc Natl Acad Sci USA 97: 436–441.[Abstract/Free Full Text]

Harriman JF, Liu XL, Aleo MD, Machaca K, and Schnellmann RG (2002) Endoplasmic reticulum Ca²⁺ signaling and calpains mediate renal cell death. Cell Death Differ 9: 734–741.[CrossRef][Medline]

Irving EA, Barone FC, Reith AD, Hadingham SJ, and Parsons AA (2000) Differential activation of MAPK/ERK and p38/SAPK in neurones and glia following focal cerebral ischaemia in the rat. Brain Res Mol Brain Res 77: 65–75.[Medline]

Ishikawa Y and Kitamura M (2000) Anti-apoptotic effect of quercetin: intervention in the JNK- and ERK-mediated apoptotic pathways. Kidney Int 58: 1078–1087.[CrossRef][Medline]

Jo SK, Cho WY, Sung SA, Kim HK, and Won NH (2005) MEK inhibitor, U0126, attenuates cisplatin-induced renal injury by decreasing inflammation and apoptosis. Kidney Int 67: 458–466.[CrossRef][Medline]

Kamakura S, Moriguchi T, and Nishida E (1999) Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. Identification and characterization of a signaling pathway to the nucleus. J Biol Chem 274: 26563–26571.[Abstract/Free Full Text]

Kim GS, Hong JS, Kim SW, Koh JM, An CS, Choi JY, and Cheng SL (2003) Leptin induces apoptosis via ERK/cPLA2/cytochrome c pathway in human bone marrow stromal cells. J Biol Chem 278: 21920–21929.[Abstract/Free Full Text]

Kim R, Emi M, Tanabe K, Murakami S, Uchida Y, and Arihiro K (2006) Regulation and interplay of apoptotic and non-apoptotic cell death. J Pathol 208: 319–326.[CrossRef][Medline]

Kim YK, Kim HJ, Kwon CH, Kim JH, Woo JS, Jung JS, and Kim JM (2005) Role of ERK activation in cisplatin-induced apoptosis in OK renal epithelial cells. J Appl Toxicol 25: 374–382.[CrossRef][Medline]

Kohda Y, Hiramatsu J, and Gemba M (2003) Involvement of MEK/ERK pathway in cephaloridine-induced injury in rat renal cortical slices. Toxicol Lett 143: 185–194.[CrossRef][Medline]

Kohda Y, Kawai Y, Iwamoto N, Matsunaga Y, Aiga H, Awaya A, and Gemba M (2005) Serum thymic factor, FTS, attenuates cisplatin nephrotoxicity by suppressing cisplatin-induced ERK activation. Biochem Pharmacol 70: 1408–1416.[CrossRef][Medline]

Kulich SM and Chu CT (2001) Sustained extracellular signal-regulated kinase activation by 6-hydroxydopamine: implications for Parkinson's disease. J Neurochem 77: 1058–1066.[CrossRef][Medline]

Kyosseva SV (2004) Mitogen-activated protein kinase signaling. Int Rev Neurobiol 59: 201–220.[Medline]

Lee JS, Kim SY, Kwon CH, and Kim YK (2005) EGFR-dependent ERK activation triggers hydrogen peroxide-induced apoptosis in OK renal epithelial cells. Arch Toxicol 80: 337–346.[Medline]

Lee SR and Lo EH (2003) Interactions between p38 mitogen-activated protein kinase and caspase-3 in cerebral endothelial cell death after hypoxia-reoxygenation. Stroke 34: 2704–2709.[Abstract/Free Full Text]

Lesuisse C and Martin LJ (2002) Immature and mature cortical neurons engage different apoptotic mechanisms involving caspase-3 and the mitogen-activated protein kinase pathway. J Cereb Blood Flow Metab 22: 935–950.[CrossRef][Medline]

Leu JI, Dumont P, Hafey M, Murphy ME, and George DL (2004) Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex. Nat Cell Biol 6: 443–450.[CrossRef][Medline]

Li DW, Liu JP, Mao YW, Xiang H, Wang J, Ma WY, Dong Z, Pike HM, Brown RE, and Reed JC (2005) Calcium-activated RAF/MEK/ERK signaling pathway mediates p53-dependent apoptosis and is abrogated by alpha B-crystallin through inhibition of RAS activation. Mol Biol Cell 16: 4437–4453.[Abstract/Free Full Text]

Li H, Zhu H, Xu CJ, and Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94: 491–501.[CrossRef][Medline]

Liu X, Van Vleet T, and Schnellmann RG (2004) The role of calpain in oncotic cell death. Annu Rev Pharmacol Toxicol 44: 349–370.[CrossRef][Medline]

Magnuson NS, Beck T, Vahidi H, Hahn H, Smola U, and Rapp UR (1994) The Raf-1 serine/threonine protein kinase. Semin Cancer Biol 5: 247–253.[Medline]

Majno G and Joris I (1995) Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 146: 3–15.[Abstract]

Matsunaga Y, Kawai Y, Kohda Y, and Gemba M (2005) Involvement of activation of NADPH oxidase and extracellular signal-regulated kinase (ERK) in renal cell injury induced by zinc. J Toxicol Sci 30: 135–144.[CrossRef][Medline]

Medina MG, Ledesma MD, Dominguez JE, Medina M, Zafra D, Alameda F, Dotti CG, and Navarro P (2005) Tissue plasminogen activator mediates amyloid-induced neurotoxicity via Erk1/2 activation. EMBO (Eur Mol Biol Organ) J 24: 1706–1716.[CrossRef][Medline]

Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, and Moll UM (2003) p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11: 577–590.[CrossRef][Medline]

Miyajima A, Nakashima J, Yoshioka K, Tachibana M, Tazaki H, and Murai M (1997) Role of reactive oxygen species in cis-dichlorodiammineplatinum-induced cytotoxicity on bladder cancer cells. Br J Cancer 76: 206–210.[Medline]

Moll UM, Wolff S, Speidel D, and Deppert W (2005) Transcription-independent pro-apoptotic functions of p53. Curr Opin Cell Biol 17: 631–636.[CrossRef][Medline]

Mori T, Wang X, Jung JC, Sumii T, Singhal AB, Fini ME, Dixon CE, Alessandrini A, and Lo EH (2002) Mitogen-activated protein kinase inhibition in traumatic brain injury: in vitro and in vivo effects. J Cereb Blood Flow Metab 22: 444–452.[CrossRef][Medline]

Namura S, Iihara K, Takami S, Nagata I, Kikuchi H, Matsushita K, Moskowitz MA, Bonventre JV, and Alessandrini A (2001) Intravenous administration of MEK inhibitor U0126 affords brain protection against forebrain ischemia and focal cerebral ischemia. Proc Natl Acad Sci USA 98: 11569–11574.[Abstract/Free Full Text]

Nowak G (2002) Protein kinase C-alpha and ERK1/2 mediate mitochondrial dys-function, decreases in active Na⁺ transport, and cisplatin-induced apoptosis in renal cells. J Biol Chem 277: 43377–43388.[Abstract/Free Full Text]

Park BG, Yoo CI, Kim HT, Kwon CH, and Kim YK (2005) Role of mitogen-activated protein kinases in hydrogen peroxide-induced cell death in osteoblastic cells. Toxicology 215: 115–125.[CrossRef][Medline]

Park KM, Chen A, and Bonventre JV (2001) Prevention of kidney ischemia/reperfusion-induced functional injury and JNK, p38, and MAPK kinase activation by remote ischemic pretreatment. J Biol Chem 276: 11870–11876.[Abstract/Free Full Text]

Pavlovic D, Andersen NA, Mandrup-Poulsen T, and Eizirik DL (2000) Activation of extracellular signal-regulated kinase (ERK)1/2 contributes to cytokine-induced apoptosis in purified rat pancreatic beta-cells. Eur Cytokine Netw 11: 267–274.[Medline]

Persons DL, Yazlovitskaya EM, and Pelling JC (2000) Effect of extracellular signal-regulated kinase on p53 accumulation in response to cisplatin. J Biol Chem 275: 35778–35785.[Abstract/Free Full Text]

Petros AM, Gunasekera A, Xu N, Olejniczak ET, and Fesik SW (2004) Defining the p53 DNA-binding domain/Bcl-x_L-binding interface using NMR. FEBS Lett 559: 171–174.[CrossRef][Medline]

Peyssonnaux C and Eychene A (2001) The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell 93: 53–62.[CrossRef][Medline]

Pi X, Yan C, and Berk BC (2004) Big mitogen-activated protein kinase (BMK1)/ERK5 protects endothelial cells from apoptosis. Circ Res 94: 362–369.[Abstract/Free Full Text]

Ramachandiran S, Huang Q, Dong J, Lau SS, and Monks TJ (2002) Mitogen-activated protein kinases contribute to reactive oxygen species-induced cell death in renal proximal tubule epithelial cells. Chem Res Toxicol 15: 1635–1642.[CrossRef][Medline]

Rennefahrt U, Janakiraman M, Ollinger R, and Troppmair J (2005) Stress kinase signaling in cancer: fact or fiction? Cancer Lett 217: 1–9.[CrossRef][Medline]

Roux PP and Blenis J (2004) ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68: 320–344.[Abstract/Free Full Text]

Runden E, Seglen PO, Haug FM, Ottersen OP, Wieloch T, Shamloo M, and Laake JH (1998) Regional selective neuronal degeneration after protein phosphatase inhibition in hippocampal slice cultures: evidence for a MAP kinase-dependent mechanism. J Neurosci 18: 7296–7305.[Abstract/Free Full Text]

Sasada T, Iwata S, Sato N, Kitaoka Y, Hirota K, Nakamura K, Nishiyama A, Taniguchi Y, Takabayashi A, and Yodoi J (1996) Redox control of resistance to cis-diamminedichloroplatinum (II) (CDDP): protective effect of human thioredoxin against CDDP-induced cytotoxicity. J Clin Investig 97: 2268–2276.[Medline]

Sinha D, Bannergee S, Schwartz JH, Lieberthal W, and Levine JS (2004) Inhibition of ligand-independent ERK1/2 activity in kidney proximal tubular cells deprived of soluble survival factors up-regulates Akt and prevents apoptosis. J Biol Chem 279: 10962–10972.[Abstract/Free Full Text]

Slevin M, Krupinski J, Slowik A, Rubio F, Szczudlik A, and Gaffney J (2000) Activation of MAP kinase (ERK-1/ERK-2), tyrosine kinase and VEGF in the human brain following acute ischaemic stroke. Neuroreport 11: 2759–2764.[Medline]

Strniskova M, Barancik M, and Ravingerova T (2002) Mitogen-activated protein kinases and their role in regulation of cellular processes. Gen Physiol Biophys 21: 231–255.[Medline]

Sturla LM, Cowan CW, Guenther L, Castellino RC, Kim JY, and Pomeroy SL (2005) A novel role for extracellular signal-regulated kinase 5 and myocyte enhancer factor 2 in medulloblastoma cell death. Cancer Res 65: 5683–5689.[Abstract/Free Full Text]

Subramaniam S, Strelau J, and Unsicker K (2003) Growth differentiation factor-15 prevents low potassium-induced cell death of cerebellar granule neurons by differential regulation of Akt and ERK pathways. J Biol Chem 278: 8904–8912.[Abstract/Free Full Text]

Subramaniam S, Zirrgiebel U, von Bohlen Und Halbach O, Strelau J, Laliberte C, Kaplan DR, and Unsicker K (2004) ERK activation promotes neuronal degeneration predominantly through plasma membrane damage and independently of caspase-3. J Cell Biol 165: 357–369.[Abstract/Free Full Text]

Sugino T, Nozaki K, Takagi Y, Hattori I, Hashimoto N, Moriguchi T, and Nishida E (2000) Activation of mitogen-activated protein kinases after transient forebrain ischemia in gerbil hippocampus. J Neurosci 20: 4506–4514.[Abstract/Free Full Text]

Suzaki Y, Yoshizumi M, Kagami S, Koyama AH, Taketani Y, Houchi H, Tsuchiya K, Takeda E, and Tamaki T (2002) Hydrogen peroxide stimulates c-Src-mediated big mitogen-activated protein kinase 1 (BMK1) and the MEF2C signaling pathway in PC12 cells: potential role in cell survival following oxidative insults. J Biol Chem 277: 9614–9621.[Abstract/Free Full Text]

Tikoo K, Lau SS, and Monks TJ (2001) Histone H3 phosphorylation is coupled to poly-(ADP-ribosylation) during reactive oxygen species-induced cell death in renal proximal tubular epithelial cells. Mol Pharmacol 60: 394–402.[Abstract/Free Full Text]

Ulisse S, Cinque B, Silvano G, Rucci N, Biordi L, Cifone MG, and D'Armiento M (2000) Erk-dependent cytosolic phospholipase A2 activity is induced by CD95 ligand cross-linking in the mouse derived Sertoli cell line TM4 and is required to trigger apoptosis in CD95 bearing cells. Cell Death Differ 7: 916–924.[CrossRef][Medline]

Vossler MR, Yao H, York RD, Pan MG, Rim CS, and Stork PJ (1997) cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway. Cell 89: 73–82.[CrossRef][Medline]

Wang X, Martindale JL, and Holbrook NJ (2000) Requirement for ERK activation in cisplatin-induced apoptosis. J Biol Chem 275: 39435–39443.[Abstract/Free Full Text]

Wang X, Wang H, Xu L, Rozanski DJ, Sugawara T, Chan PH, Trzaskos JM, and Feuerstein GZ (2003) Significant neuroprotection against ischemic brain injury by inhibition of the MEK1 protein kinase in mice: exploration of potential mechanism associated with apoptosis. J Pharmacol Exp Ther 304: 172–178.[Abstract/Free Full Text]

Wang ZQ, Chen XC, Yang GY, and Zhou LF (2004a) U0126 prevents ERK pathway phosphorylation and interleukin-1beta mRNA production after cerebral ischemia. Chin Med Sci J 19: 270–275.[Medline]

Wang ZQ, Wu DC, Huang FP, and Yang GY (2004b) Inhibition of MEK/ERK 1/2 pathway reduces pro-inflammatory cytokine interleukin-1 expression in focal cerebral ischemia. Brain Res 996: 55–66.[CrossRef][Medline]

Woessmann W, Chen X, and Borkhardt A (2002) Ras-mediated activation of ERK by cisplatin induces cell death independently of p53 in osteosarcoma and neuroblastoma cell lines. Cancer Chemother Pharmacol 50: 397–404.[CrossRef][Medline]

Wong JK, Le HH, Zsarnovszky A, and Belcher SM (2003) Estrogens and ICI182,780 (Faslodex) modulate mitosis and cell death in immature cerebellar neurons via rapid activation of p44/p42 mitogen-activated protein kinase. J Neurosci 23: 4984–4995.[Abstract/Free Full Text]

Wu Z, Wu LJ, Tashiro S, Onodera S, and Ikejima T (2005) Phosphorylated extracellular signal-regulated kinase up-regulated p53 expression in shikonin-induced HeLa cell apoptosis. Chin Med J (Engl) 118: 671–677.[Medline]

Yang JY, Michod D, Walicki J, and Widmann C (2004) Surviving the kiss of death. Biochem Pharmacol 68: 1027–1031.[CrossRef][Medline]

Yoon S and Seger R (2006) The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 24: 21–44.[Medline]

Yu SP (2003) Regulation and critical role of potassium homeostasis in apoptosis. Prog Neurobiol 70: 363–386.[CrossRef][Medline]

Yu SP, Canzoniero LM, and Choi DW (2001) Ion homeostasis and apoptosis. Curr Opin Cell Biol 13: 405–411.[CrossRef][Medline]

Zhou G, Bao ZQ, and Dixon JE (1995) Components of a new human protein kinase signal transduction pathway. J Biol Chem 270: 12665–12669.[Abstract/Free Full Text]

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