Activation of Stress Signaling Pathways by the End Product of Lipid Peroxidation

Uchida, Koji; Shiraishi, Mihoko; Naito, Yuko; Torii, Yasuyoshi; Nakamura, Yoshimasa; Osawa, Toshihiko

doi:10.1074/jbc.274.4.2234

Cited by 538 publications

(168 citation statements)

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“…HNE did not inhibit any of these upstream kinases, and in fact, a brief survey indicated that it stimulated the activity of ERK1, ERK2, JNK1, and JNK2 (data not shown). This is consistent with a previous finding of stimulation of p38 kinase activity by HNE (42).…”

Section: Discussionsupporting

confidence: 83%

IκB Kinase, a Molecular Target for Inhibition by 4-Hydroxy-2-nonenal

Kozak

Marnett

2001

Journal of Biological Chemistry

186

153

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Aldehydes are products and propagators of oxidative stress (1). They are reactive electrophiles that form adducts to protein and DNA that have been detected in tissues from healthy human beings and individuals with various diseases (2-6). Consequently, aldehydes modulate the activities of numerous proteins, induce mutations, and alter cell cycle progression (7-12). For example, malondialdehyde, a major carbonyl product of lipid peroxidation, is mutagenic and carcinogenic and induces cell cycle arrest at the G 1 /S and G 2 /M checkpoints (7). The G 1 /S arrest in human colon and lung cancer cells (RKO and H1299, respectively) is caused by induction of the cyclin-dependent kinase inhibitor, p21, whereas the G 2 /M arrest appears to be due to a reduction in the level of the cdc2 kinase. Thus, alteration of gene expression triggered by protein or DNA damage may contribute to the range of biological effects exerted by aldehydes.A panoply of pathophysiological responses is also exerted by 4-hydroxynonenal (HNE), 1 the major toxic product of lipid peroxidation (1). HNE reacts with sulfhydryl and amino groups and leads to inactivation of DNA polymerases, dehydrogenases, and various transporters, inter alia (13). It also causes cell cycle arrest and apoptosis (8 -10). HNE treatment of cells alters the expression of several transcription factors including c-Myc (12), c-Myb (14), and c-Jun (15), suggesting that it may have more global effects on protein expression and cell function. The induction of c-Jun by HNE is associated with activation of JNK kinase and p38 kinase, perhaps by H 2 O 2 modulation of upstream signaling pathways (15, 16).A major signaling pathway associated with inflammation and oxidative stress is mediated by the transcription factor NF-B (17-19). NF-B consists of heterodimers of two polypeptides, p50 and p65, which are members of a family of proteins related to the proto-oncogene c-rel (20, 21). Inactive NF-B is located in the cytosol, bound to its inhibitory protein, IB. Dissociation of NF-B from IB is a critical step in NF-B activation that leads to translocation of NF-B to the nucleus, enabling DNA binding and transactivation (22). This process is triggered by sequential phosphorylation and ubiquitination of IB␣, followed by digestion of the ubiquinated protein by the proteasome (23-25). The enzyme that catalyzes the ubiquitination of phosphorylated IB is constitutively active. Hence, in most cases, the key event for NF-B activation is phosphorylation of two serine residues at the N terminus of IB by IB kinase (IKK) (23,24).We report here that treatment of RKO and H1299 cells with HNE leads to a dramatic loss of DNA binding and transcriptional activation by NF-B in cells treated with tetradecanoylphorbol acetate (TPA) and ionomycin (IM). The loss of NF-B activity is due to stabilization to the IB␣-NF-B complex, which results from a decrease in the rate of turnover of IB␣. The prevention of IB␣ turnover is attributable to the inhibition of IKK caused by direct reaction with HNE. These findings indica...

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Section: Discussionsupporting

confidence: 83%

IκB Kinase, a Molecular Target for Inhibition by 4-Hydroxy-2-nonenal

Kozak

Marnett

2001

Journal of Biological Chemistry

186

153

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“…This strengthens the prospect of a mechanism that acts through inhibition of survival signaling rather than stimulation of death signaling. Quercetin has been observed to suppress JNK activity induced by hydrogen peroxide (26, 28) and 4-hydroxy-2-nonenal (27), suggesting that quercetin is able to prevent stress-induced activation of JNK but not basal activation. This agrees with previous investigations where the flavonoids epicatechin, 3Ј-O-methyl epicatechin, and kaempferol inhibited JNK activation by oxidized low density lipoprotein but had no effect on basal JNK phosphorylation (41).…”

Section: Discussionmentioning

confidence: 99%

“…For example, it has been observed to induce caspase-3 activation in the malignant cell line HPB-ALL (24), activate caspase-3 and caspase-9, release cytochrome c in HL-60 cells (25), and induce chromatin and nuclear fragmentation in colonic cancer cells (20). On the other hand, quercetin treatment has been shown to suppress the c-Jun N-terminal kinase (JNK) 1 activity and apoptosis induced by hydrogen peroxide (26) and 4-hydroxy-2-nonenal (27). Furthermore, quercetin may evoke anti-apoptotic effects via the suppression of the peroxide-induced JyNK-cJun/AP-1 pathway and the ERK-c-Fos/AP-1 pathway in cultured mesangial cells (28).…”

mentioning

confidence: 99%

Modulation of Pro-survival Akt/Protein Kinase B and ERK1/2 Signaling Cascades by Quercetin and Its in Vivo Metabolites Underlie Their Action on Neuronal Viability

Spencer

Rice‐Evans

Williams

2003

Journal of Biological Chemistry

311

224

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Much recent interest has focused on the potential of flavonoids to interact with intracellular signaling pathways such as with the mitogen-activated protein kinase cascade. We have investigated whether the observed strong neurotoxic potential of quercetin in primary cortical neurons may occur via specific and sensitive interactions within neuronal mitogen-activated protein kinase and Akt/protein kinase B (PKB) signaling cascades, both implicated in neuronal apoptosis. Quercetin induced potent inhibition of both Akt/PKB and ERK phosphorylation, resulting in reduced phosphorylation of BAD and a strong activation of caspase-3. High quercetin concentrations (30 M) led to sustained loss of Akt phosphorylation and subsequent Akt cleavage by caspase-3, whereas at lower concentrations (<10 M) the inhibition of Akt phosphorylation was transient and eventually returned to basal levels. Lower levels of quercetin also induced strong activation of the pro-survival transcription factor cAMP-responsive element-binding protein, although this did not prevent neuronal damage. O-Methylated quercetin metabolites inhibited Akt/PKB to lesser extent and did not induce such strong activation of caspase-3, which was reflected in the lower amount of damage they inflicted on neurons. In contrast, neither quercetin nor its O-methylated metabolites had any measurable effect on c-Jun N-terminal kinase phosphorylation. The glucuronide of quercetin was not toxic and did not evoke any alterations in neuronal signaling, probably reflecting its inability to enter neurons. Together these data suggest that quercetin and to a lesser extent its O-methylated metabolites may induce neuronal death via a mechanism involving an inhibition of neuronal survival signaling through the inhibition of both Akt/PKB and ERK rather than by an activation of the c-Jun N-terminal kinase-mediated death pathway.

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“…5) Among the aldehydes generated as the result of membrane lipid peroxidation, HNE can be produced in relatively large concentrations up to 5 mM in cells, and is the most damaging to cells. 3,6) Koster et al also reported that the concentration of HNE in the lipid bilayer of peroxidized microsomes is about 4.5 mM. 7) HNE directly interacts with several amino acid residues of protein, i.e., the sulfhydryl (SH) group of cysteine, the imidazole moiety of histidine and the e-amino group of lysine through a Michael-type nucleophilic addition.…”

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confidence: 99%