A Death-Promoting Role for Extracellular Signal-Regulated Kinase

Abstract

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.

Evidence that Cisplatin-induced Auditory Damage is Attenuated by Downregulation of Pro-inflammatory Cytokines Via Nrf2/HO-1

“…Anti-apoptotic effects of ERK activation against a diverse range of apoptotic signals, including serum-deprivation-induced apoptosis of PC12 cells (Yan and Greene 1998) and TNF-α-induced apoptosis of L929 cells (Gardner and Johnson 1996), have been reported. Apoptosis signaling through ERK activation have also been described (Zhuang and Schnellmann 2006). In a mouse model of cisplatin-induced nephrotoxicity, ERK activation was observed in distal tubules and collecting ducts of kidney after cisplatin administration.…”

Chemosensitisation by manganese superoxide dismutase inhibition is caspase-9 dependent and involves extracellular signal-regulated kinase 1/2

“…It has also been postulated that MnSOD via O 2 KÀ elimination to regulate cell proliferation and tumourigenesis through the activation of Ras-mediated signalling pathway (Yang et al, 1999;Ridnour et al, 2004). How ERK1/2 mediates cellular apoptosis remains poorly understood, but it appears that this may occur at different levels (Zhuang and Schnellmann, 2006). Extracellular signal-regulated kinase 1/2 may act upstream of mitochondrial cytochrome c release and caspase-3 activation through upregulation of Bax and p53.…”

p53 Protein-mediated Up-regulation of MAP Kinase Phosphatase 3 (MKP-3) Contributes to the Establishment of the Cellular Senescent Phenotype through Dephosphorylation of Extracellular Signal-regulated Kinase 1/2 (ERK1/2)

“…In addition to proliferation, ERK1/2 also controls cell survival (58,59). ERK1/2 mediates the extracellular stimulus-elicited activation of cellular intrinsic and extrinsic apoptotic signaling pathways (60).…”