Independent regulation of JNK/p38 mitogen-activated protein kinases by metabolic oxidative stress in the liver

Kg, Mendelson; Lr, Contois; Sg, Tevosian; Davis, RJ; Ke, Paulson

doi:10.1073/pnas.93.23.12908

Cited by 219 publications

(156 citation statements)

References 42 publications

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“…A transient increase in JNK activation has also been observed with other agents that either fail to induce or at least have a minimal e ect in cell death such as cytokines (Su et al, 1994;Chen et al, 1996a) and in our hands also trans-DDP. As previously described for gamma radiation (Chen et al, 1996a,b), oxidative stress (Mendelson et al, 1996) and high doses of U.V.C light (Chen et al, 1996b), cis-DDP induces a late and sustained activation of JNK activity that as with other types of stress, correlate with apoptosis.…”

Section: Cis-ddp Induces a Persistent Activation Of Jnk But Not Mapksupporting

confidence: 54%

Cisplatin induces a persistent activation of JNK that is related to cell death

1998

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Genotoxic stress triggers signalling pathways that either mediate cell killing or protection of a ected cells. While induction of p53 is observed for most of the genotoxins, activation of MAPK/SAPK cascades is not a general response. The role of MAPK/SAPK activation on cell fate, seems to be dependent, in some systems, on the balanced response among both cascades. We have here examined the e ect of cis and trans-DDP on the activation of ERK and JNK activities. While no signi®cant induction of ERK was observed with the compounds, both of them are able to strongly activate JNK. Trans-DDP response is rapid and transient while the cis-DDP one is slow and persistent. In contrast with the observed nuclear translocation of JNK in response to U.V. light, none of the platinum compounds induces translocation, on the contrary, activation of JNK occurs in both the nuclear and cytoplasmic compartments. Inhibition of tyrosine phosphatases by orthovanadate pretreatment prolongs the time of JNK induction in response to both platinum compounds. The positive modulation of JNK activation correlates with an increase in toxicity that, for cis-DDP corresponds to a tenfold decrease in the IC 50 . A strong increase in MKP-1 levels was observed only in response to trans-DDP suggesting the involvement of this activity in the downregulation of JNK activity in response to this compound. Altogether the results suggest that the prolonged activation of JNK in response to cis-DDP contributes to cell death induction.

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Section: Cis-ddp Induces a Persistent Activation Of Jnk But Not Mapksupporting

confidence: 54%

Cisplatin induces a persistent activation of JNK that is related to cell death

1998

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“…Stress-responsive protein kinase p38, a member of the mitogen-activated protein kinase family, may also inhibit cyclin D1 37 and is activated by ROS in liver tissue. 7 We found that phosphorylated p38 levels rapidly increased after partial hepatectomy both in the absence and presence of UCP2, but remained at higher levels for a longer period in UCP2 Ϫ/Ϫ liver remnants than in UCP2 ϩ/ϩ controls (Fig. 3C).…”

Section: Resultsmentioning

confidence: 74%

“…4,5 ROS are known to mediate cell growth arrest 5 and activate proteins that inhibit the cell cycle. 6,7 Therefore, ROS production in the liver remnant is likely to have a role in the negative control of regeneration.…”

mentioning

confidence: 99%

Uncoupling protein-2 deficiency promotes oxidant stress and delays liver regeneration in mice

et al. 2004

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The control of liver regeneration remains elusive. Because reactive oxygen species (ROS) are able to mediate cell growth arrest and activate proteins that inhibit the cell cycle, ROS production may have a negative impact on liver regeneration. We examined how liver regeneration is affected by uncoupling protein-2 (UCP2), an inner mitochondrial membrane carrier that senses and negatively regulates superoxide production. Liver regeneration was monitored up to 5 days and was found to be significantly delayed in UCP2 ؊/؊ mice after partial hepatectomy. Apoptosis rates in UCP2 ؉/؉ and UCP2 ؊ /؊ liver remnants were similar, while parameters of cell proliferation indicated a diminished response in UCP2 ؊ /؊ mice with corresponding changes in the expression of key cell cycle regulatory proteins and prolonged activation of stress-responsive protein kinase p38. Levels of malondialdehyde, a marker of ROS generation and oxidant stress, were elevated in UCP2 ؊ /؊ livers at every examined time point. Liver remnants of UCP2 ؉ /؉ mice 48 hours post-hepatectomy showed a fourfold increase in the expression of UCP2 protein primarily detected in hepatocytes. In conclusion, our results suggest that absent or insufficient UCP2 function in the regenerating liver results in increased ROS production and negatively modulates the control of cell cycle.

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“…These data are in line with the observation that p38 MAPK function was down-regulated through selective dephosphorylation after oxidative stress because of rapid stress-induced activation of the phosphatase MKP-1 in vivo. 40 However, we cannot exclude the possibility that intracellular S100A8 Fig. 8.…”

Section: Discussionmentioning

confidence: 92%

S100A8 and S100A9 are novel nuclear factor kappa B target genes during malignant progression of murine and human liver carcinogenesis

et al. 2009

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The nuclear factor-kappaB (NF-B) signaling pathway has been recently shown to participate in inflammation-induced cancer progression. Here, we describe a detailed analysis of the NF-B-dependent gene regulatory network in the well-established Mdr2 knockout mouse model of inflammation-associated liver carcinogenesis. Expression profiling of NF-B-deficient and NF-B-proficient hepatocellular carcinoma (HCC) revealed a comprehensive list of known and novel putative NF-B target genes, including S100a8 and S100a9. We detected increased co-expression of S100A8 and S100A9 proteins in mouse HCC cells, in human HCC tissue, and in the HCC cell line Hep3B on ectopic RelA expression. Finally, we found a synergistic function for S100A8 and S100A9 in Hep3B cells resulting in a significant induction of reactive oxygen species (ROS), accompanied by enhanced cell survival. Conclusion: We identified S100A8 and S100A9 as novel NF-B target genes in HCC cells during inflammation-associated liver carcinogenesis and provide experimental evidence that increased co-expression of both proteins supports malignant progression by activation of ROS-dependent signaling pathways and protection from cell death. (HEPATOLOGY 2009;50: 1251-1262.)H epatocellular carcinoma (HCC) is the most frequent type of liver cancer and one of the most prevalent causes of cancer mortality worldwide. These tumors arise at sites of chronic liver injury, inflammation, and hepatocyte proliferation provoked by several causes such as chronic hepatitis B and C viral infection, chronic alcohol consumption, and aflatoxin B1-contaminated food. 1,2 Despite remarkable improvements in diagnosis, only limited therapeutic options exist, most of them with minimal clinical benefit. 2 Moreover, there is

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Independent regulation of JNK/p38 mitogen-activated protein kinases by metabolic oxidative stress in the liver

Cited by 219 publications

References 42 publications

Cisplatin induces a persistent activation of JNK that is related to cell death

Cisplatin induces a persistent activation of JNK that is related to cell death

Uncoupling protein-2 deficiency promotes oxidant stress and delays liver regeneration in mice

S100A8 and S100A9 are novel nuclear factor kappa B target genes during malignant progression of murine and human liver carcinogenesis

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