Cytoplasmic Retention of Peroxide-Activated ERK Provides Survival in Primary Cultures of Rat Hepatocytes *

Rosseland, Carola M.; Wierød, Lene; Oksvold, Morten P.; Werner, Heidi; Østvold, Anne Carine; Thoresen, G. Hege; Paulsen, Ragnhild E.; Huitfeldt, Henrik S.; Skarpen, Ellen

doi:10.1002/hep.20762

Cited by 61 publications

(70 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Restriction in the cytoplasm of activated ERK1/2 is important for hepatocyte survival following H 2 O 2 treatment (39). On the other hand, persistent nuclear retention of activated ERK1/2 is reported in eliciting pro-apoptosis in glutamate-treated neurons (22).…”

Section: Nhe1 Activity Is Stimulated In Cortical Neurons Aftermentioning

confidence: 99%

ERK1/2-p90RSK-mediated Phosphorylation of Na+/H+ Exchanger Isoform 1

Luo

Kintner

Shull

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

The function and regulation of Na ؉ /H ؉ exchanger isoform 1 (NHE1) following cerebral ischemia are not well understood. In this study, we demonstrate that extracellular signal-related kinases (ERK1/2) play a role in stimulation of neuronal NHE1 following in vitro ischemia. NHE1 activity was significantly increased during 10 -60 min reoxygenation (REOX) after 2-h oxygen and glucose deprivation (OGD). OGD/REOX not only increased the V max for NHE1 but also shifted the K m toward decreased [H ؉ ] i . These changes in NHE1 kinetics were absent when MAPK/ERK kinase (MEK) was inhibited by the MEK inhibitor U0126. There were no changes in the levels of phosphorylated ERK1/2 (p-ERK1/2) after 2 h OGD. The p-ERK1/2 level was significantly increased during 10 -60 min REOX, which was accompanied by nuclear translocation. U0126 abolished REOX-induced elevation and translocation of p-ERK1/2. We further examined the ERK/90-kDa ribosomal S6 kinase (p90 RSK ) signaling pathways. At 10 min REOX, phosphorylated NHE1 was increased with a concurrent elevation of phosphorylation of p90 RSK , a known NHE1 kinase. Inhibition of MEK activity with U0126 abolished phosphorylation of both NHE1 and p90 RSK . Moreover, neuroprotection was observed with U0126 or genetic ablation or pharmacological inhibition of NHE1 following OGD/REOX. Taken together, these results suggest that activation of ERK1/2-p90 RSK pathways following in vitro ischemia phosphorylates NHE1 and increases its activity, which subsequently contributes to neuronal damage. The Naϩ /H ϩ exchanger (NHE) 2 family is a group of membrane transport proteins that catalyzes the secondary active electroneurtral exchange of one Na ϩ for one H ϩ . To date, nine NHE isoforms (NHE1-9) have been cloned in mammalian tissues (1). Na ϩ /H ϩ exchanger isoform 1 (NHE1) is the most abundant NHE isoform in the rat central nervous system (2) and crucial in regulation of neuronal pH i (3, 4). We have recently reported that NHE1 activity plays an important role in neuronal damage in both in vitro and in vivo ischemic models (4). Inhibition of NHE1 activity during OGD/REOX prevents intracellular Na ϩ and Ca 2ϩ overload and thus reduces the Ca 2ϩ -mediated cascade of deleterious events (4). In acutely isolated CA1 neurons, an anoxia-triggered intracellular alkalization depends on activation of NHE1 (5). We also found that NHE1 activity is stimulated in cortical astrocytes following in vitro ischemia (6). However, whether NHE1 activity is overstimulated in cortical neurons following in vitro ischemia remains unknown.NHE1 has two large functional domains. The N-terminal transmembrane domain (ϳ500 amino acids) is responsible for cation translocation, and the cytoplasmic C-terminal domain (ϳ315 amino acids) is the main regulatory site for the NHE1 activity (7). The distal C-terminal tail of NHE1 contains a number of serine and threonine residues that are phosphorylated by several protein kinases, including extracellular signal-related kinases (ERK1/2) and 90-kDa ribosomal S6 kinase (p90 RSK ) (8). Activa...

show abstract

Section: Nhe1 Activity Is Stimulated In Cortical Neurons Aftermentioning

confidence: 99%

ERK1/2-p90RSK-mediated Phosphorylation of Na+/H+ Exchanger Isoform 1

Luo

Kintner

Shull

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…In line with this, in mouse hippocampal cells it was found that nuclear retention of ERK caused by toxic stimuli promoted cell death (Stanciu and DeFranco, 2002). Similarly, in hydrogen peroxide-exposed rat hepatocytes, ERK, which promoted cell survival, remained cytoplasmic and there it activated the prosurvival ribosomal 6 kinase, which then translocated to the nucleus (Rosseland et al, 2005). Furthermore, several studies have shown that ERK retention in the cytosol induces growth arrest (Brunet et al, 1999;Formstecher et al, 2001;Marenda et al, 2006;Smith et al, 2004), which would seem appropriate in the face of stressful conditions possibly leading to DNA damage.…”

Section: Stimulus-and Cell Type-specific Response Of Erkmentioning

confidence: 69%

“…Nevertheless, we saw that Cu caused an increase of pERK levels in hepatocytes, whereas in the cell lines pERK was slightly diminished (RTgill-W1 cells) or unaltered (RTH-149). Generally, ERK is believed to play a dual role during toxic insults, either promoting cell survival (Czaja et al, 2003;Rosseland et al, 2005) or favouring cell death (Chu et al, 2004;Park et al, 2005;Seo et al, 2001;Wang et al, 2000). A recent study on trout hepatocytes suggests that enhanced ERK activity is detrimental during Cu 2+ exposure (Nawaz et al, 2006).…”

Section: Stimulus-and Cell Type-specific Response Of Erkmentioning

confidence: 99%

“…Mitogen-activated protein (MAP) kinases are serine/ threonine kinases activated in response to a variety of stimuli that mediate signal transduction from the cell surface to the nucleus as well as to cytoplasmic and membrane targets (de Nadal et al, 2002;Rosseland et al, 2005). The best studied MAP kinase pathway is that of the extracellular signal regulated protein kinases ERK1/2.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Activation and nuclear translocation of ERK in response to ligand-dependent and -independent stimuli in liver and gill cells from rainbow trout

Ebner

Blatzer

Nawaz

et al. 2007

Journal of Experimental Biology

View full text Add to dashboard Cite

SUMMARY The mitogen-activated protein kinase ERK is an important signalling molecule involved in the control of cell proliferation, differentiation and cell death, targeting molecules at the cell membrane, in the cytosol, and in the nucleus. This study investigated the activation pattern and subcellular distribution of ERK in liver and gill cells of rainbow trout upon hypo-osmotic shock, addition of epidermal growth factor (EGF) and copper treatment. It further set out to characterize the hypothetical role of nuclear-export signal(NES)-dependent relocation of ERK after nuclear entry and the potential involvement of the ERK activator MEK. Although, in primary hepatocytes, ERK was activated in all conditions in a stimulus-specific manner, it did not accumulate in the nucleus, irrespective of the absence or presence of the inhibitor of NES-dependent export leptomycin B (LB). Similarly, in trout hepatoma cells, where pERK levels increased upon osmotic and mitotic stimulation, but not after toxic insult, no significant nuclear translocation was observed. In a gill cell line, levels of pERK increased after osmotic and mitotic stimulation and showed a decrease during incubation with a toxicant. Again, none of these conditions triggered nuclear accumulation of pERK in the gill cells in the absence of LB, but in contrast to the observation in liver cells, both osmotic and mitotic stimulation caused nuclear accumulation in the presence of the inhibitor. The ERK activator MEK, which possesses a NES-sequence, was apparently not involved in nuclear export, as it did not seem to enter the nucleus. Altogether, ERK is activated in trout cells in a stimulus- and cell type-specific manner, and our data suggest that it acutely acts primarily on cytoplasmic or membrane-situated targets in liver cells,whereas it presumably triggers rapid transcriptional activities in gill cells.)

show abstract

“…1), while ERK1 was not activated. ERK is particularly sensitive to oxidative stress and is activated by 100 mM hydrogen peroxide, i.e., as low a level as 100 mM of reactive oxygen species, in cultured rat hepatocytes, 36) so it may be difficult to detect a change of 100 mM in 2,000 mM of vitamin C in the liver, even if all hydrogen peroxide caused an equivalent decrease in vitamin C. The activation of ERK has preceded the decrease in liver ascorbate level with the oxidative stress caused by carbon tetrachloride and thioacetamide. 8,9) The vitamin C level in the present study was significantly decreased in the non-ischemic region, so the notion of ERK activation in this region is reasonable.…”

Section: Discussionmentioning

confidence: 99%