Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Electrophile and free radical detoxifying enzymes including NAD(P)H:quinine oxidoreductase 1 (Nqo1) play an important role in the defense system by enhancing cellular antioxidant capacity. Chemopreventive efficacy of 3H-1,2-dithiole-3-thione (D3T) is mediated through activation of the transcription factor Nrf2 and subsequent elevation of detoxifying enzymes. In the present study, we have investigated the potential role of extracellular signal-regulated kinase (ERK) in regulation of D3T-induced and Nrf2-dependent gene expression in murine keratinocytes. Expression levels of Nqo1 were highly inducible by D3T treatment and increased nuclear levels of Nrf2 were observed in these cells. Treatment with pharmacological inhibitor of ERK1/2 largely blocked nuclear accumulation of Nrf2, ARE-driven reporter gene expression, and induction of Nqo1, as well as other phase 2 genes. Activation of ERK1/2 has been demonstrated following treatment with D3T. While, inhibitors of p38, PKC and PI3K did not affect ARE-driven gene expression. Involvement of the ERK1/2 cascade in inducible ARE-transcription activities was also observed in cells treated with other types of inducers oltipraz, sulforaphane and hydrogen peroxide. Collectively, current study suggests that phosphorylation cascade via ERK1/2 is associated with the activation process of Nrf2 and subsequent transactivation of its target gene Nqo1 following treatment with dithiolethione in murine keratinocyte.
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PMID:Induction of Nrf2-regulated genes by 3H-1, 2-dithiole-3-thione through the ERK signaling pathway in murine keratinocytes. 1785 98

Lipid peroxidation is a consequence of both normal physiology and oxidative stress that generates various reactive metabolites, a principal end product being 4-hydroxynonenal (HNE). As a diffusible electrophile, HNE reacts extensively with cellular nucleophiles. Consequently, HNE alters cellular signaling and activates the intrinsic apoptotic cascade. We have previously demonstrated that in addition to promoting apoptosis, HNE activates stress response pathways, including the antioxidant, endoplasmic reticulum stress, DNA damage, and heat shock responses. Here we demonstrate that activation of the heat shock response by HNE is dependent on the expression and nuclear translocation of heat shock factor 1 (HSF1), which promotes the expression of heat shock protein 40 (Hsp40) and Hsp70-1. Ectopic expression and immunoprecipitation of c-Myc-tagged Hsp70-1 indicates that HNE disrupts the inhibitory interaction between Hsp70-1 and HSF1, leading to the activation heat shock gene expression. Using siRNA to silence HSF1 expression, we observe that HSF1 is necessary for the induction of Hsp40 and Hsp70-1 by HNE, and the lack of Hsp expression is correlated with an increase in apoptosis. Nrf2, the transcription factor that mediates the antioxidant response, was also silenced using siRNA. Silencing Nrf2 also enhanced the cytotoxicity of HNE, but not as effectively as HSF1. Silencing HSF1 expression facilitates the activation of JNK pro-apoptotic signaling and selectively decreases expression of the anti-apoptotic Bcl-2 family member Bcl-X(L). Overexpression of Bcl-X(L) attenuates HNE-mediated apoptosis in HSF1-silenced cells. Overall, activation of HSF1 and stabilization of Bcl-X(L) mediate a protective response that may contribute significantly to the cellular biology of lipid peroxidation.
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PMID:Heat shock factor 1 attenuates 4-Hydroxynonenal-mediated apoptosis: critical role for heat shock protein 70 induction and stabilization of Bcl-XL. 1787 79

Hepatocyte growth factor (HGF) is a potent hepatocyte mitogen that exerts opposing effects depending on cell density. Glutathione (GSH) is the main non-protein thiol in mammalian cells that modulates growth and apoptosis. We previously showed that GSH level is inversely related to cell density of hepatocytes and is positively related to growth. Our current work examined whether HGF can modulate GSH synthesis in a cell density-dependent manner and how GSH in turn influence HGF's effects. We found HGF treatment of H4IIE cells increased cell GSH levels only under subconfluent density. The increase in cell GSH under low density was due to increased transcription of GSH synthetic enzymes. This correlated with increased protein levels and nuclear binding activities of c-Jun, c-Fos, p65, p50, Nrf1 and Nrf2 to the promoter region of these genes. HGF acts as a mitogen in H4IIE cells under low cell density and protects against tumor necrosis factor alpha (TNFalpha)-induced apoptosis by limiting JNK activation. However, HGF is pro-apoptotic under high cell density and exacerbates TNFalpha-induced apoptosis by potentiating JNK activation. The increase in cell GSH under low cell density allows HGF to exert its full mitogenic effect but is not necessary for its anti-apoptotic effect.
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PMID:Effects of hepatocyte growth factor on glutathione synthesis, growth, and apoptosis is cell density-dependent. 1795 Jul 27

NO (nitric oxide) biology has provided the impetus for the development of anticancer agents based on their ability to release NO. NO-NSAIDs (NO-donating non-steroidal anti-inflammatory drugs), consisting of a conventional NSAID to which an NO-releasing moiety is covalently attached, are promising chemopreventive agents against cancer. Compared with their parent compounds, NO-NSAIDs are up to several hundred times more potent in inhibiting the growth of cancer cell lines and prevent colon and pancreatic cancer in animal models. Their chemopreventive effect is due to inhibition of proliferation, induction of cell death and inhibition of cell-cycle-phase transitions. NO-ASA (NO-aspirin), the best-studied NO-NSAID, induces oxidative stress in target cells. Major downstream signalling effects involve the Wnt, NOS2 (nitric oxide synthase 2), MAPK (mitogen-activated protein kinase), NF-kappaB (nuclear factor kappaB) and Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) pathways. NO-NSAIDs, particularly NO-ASA, appear to be safe compounds, as suggested by many animal and early human studies. An ongoing clinical trial is designed to determine whether NO-ASA can inhibit early stages of colon carcinogenesis in subjects at risk for colon cancer. It is clinical trials that will ultimately determine the role of NO-NSAIDs in cancer prevention and perhaps treatment.
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PMID:Novel agents for cancer prevention based on nitric oxide. 1795 52

Heme oxygenase-1 (HO-1) is highly expressed in various tumor tissues and plays an important role in tumor cell growth through anti-oxidative and anti-apoptotic effects. Herein, we demonstrate that A549 cells express high levels of HO-1, Nrf2, and NF-kappaB compared to other lung cancer cell lines, including H23, H157, and H460. Ectopic expression of HO-1 small interfering RNA (siRNA) increased both apoptosis and degradation of procaspase-3. Transfection studies with siRNA specific for Nrf2 and NF-kappaB revealed that HO-1 expression in A549 cells is mediated by transcriptional activation of Nrf2, but not NF-kappaB. A549 cells are less susceptible to cisplatin cytotoxicity than other lung cancer cell lines, concomitant with increases in HO-1 expression and MAPK phosphorylation in a time-dependent fashion. Furthermore, inhibition of HO-1 by siRNA and a specific HO-1 inhibitor ZnPP augments cisplatin cytotoxicity toward A549 cells. Pharmacologic suppression of HO-1 activity resulted in a marked increase in the ROS generation in cisplatin-treated cells. In addition, pharmacologic inhibitors of MAPK suppressed the induction of HO-1 and Nrf2 expression by cisplatin. These findings suggest that HO-1 may modulate the chemosensitivity of lung cancer A549 cells to cisplatin through the MAPK-Nrf2 pathway.
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PMID:Suppression of Nrf2-driven heme oxygenase-1 enhances the chemosensitivity of lung cancer A549 cells toward cisplatin. 1800 13

Heme oxygenase-1 (HO-1) catalyzes the rate limiting reaction of heme metabolism and plays critical roles in resistance to oxidative stress and other cellular functions. It is well known that HO-1 is induced in response to various stresses; however, the signaling pathways involved remain incompletely elucidated. Acrolein is an alpha,beta-unsaturated aldehyde present in cigarette smoke and also a product of lipid peroxidation. In this investigation we studied HO-1 induction in response to acrolein and determined the signaling pathways involved in human bronchial epithelial cells (HBE1 cells). We demonstrated that acrolein significantly increased the HO-1 mRNA content and promoter activity. Acrolein-mediated HO-1 induction was significantly attenuated by pan-protein kinase C (PKC) inhibitors RO318220, staurosporine, and PKC-delta selective inhibitor rottlerin and PKC-delta small interfering RNA. The HO-1 induction was also decreased by phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 and wortmannin. No significant effects on HO-1 induction were observed with the pretreatment of mitogen-activated protein kinase pathway inhibitors PD98059 (ERK), SB203580 (p38MAPK) and JNKi, and conventional and atypical PKC inhibitors. Furthermore, Nrf2 silencing significantly attenuated the HO-1 induction by acrolein. Inhibition of PKC-delta significantly decreased acrolein-mediated Nrf2 nuclear translocation, though inhibition of PI3K had no effect. Taken together, our results indicate that acrolein up-regulates HO-1 expression through both PKC-delta and PI3K pathways in HBE1 cells; PKC-delta appears to regulate HO-1 induction via modulating Nrf2 nuclear translocation, while PI3K may work through targeting on downstream signaling molecules other than Nrf2.
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PMID:Acrolein induces heme oxygenase-1 through PKC-delta and PI3K in human bronchial epithelial cells. 1804 4

The Nrf2/ARE pathway plays a pivotal role in chemoprevention and neuroprotection. Here, we report that sesquiterpene lactones extracted from Calea urticifolia and feverfew increased enhancer activity of the ARE. ARE activation was dependent on the number of alpha,beta-unsaturated carbonyl groups each compound bears and calealactone A (CL-A) harboring 3 of those was the most potent ARE inducer. At subtoxic doses, CL-A induced expression of heme oxygenase-1 (HO-1) gene, one of ARE target genes, through activation of the Nrf2/ARE pathway involving transient ROS generation and activation of PI3-K/Akt and MAPK pathways. Interestingly, H(2)O(2)-induced ARE activation and HO-1 induction were potentiated by pretreatment with CL-A at lower concentrations, at which Nrf2/ARE activation by the compound was minimal. These results suggest a possibility that preconditioning by sesquiterpene lactone may enhance activation of the Nrf2/ARE pathway and induction of phase II detoxification/antioxidant enzymes upon oxidative stress, thereby resulting in increased resistance to oxidative damage.
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PMID:Preconditioning by sesquiterpene lactone enhances H2O2-induced Nrf2/ARE activation. 1827 57

Heme oxygenase-1 (HO-1) is markedly upregulated by sodium arsenite and previous studies implicated the transcriptional enhancers Nrf2 and AP-1 in arsenite-induced ho-1 gene expression in murine cells. To further evaluate the role of Nrf2 and its signalling pathway in the induction of HO-1 in response to low levels of arsenite, this paper studied wild-type and Nrf2-deficient murine embryonic fibroblasts. It was found that Nrf2 plays a crucial role in the early activation of ho-1 transcription and that increased Nrf2 levels returned to basal levels within 24 h. In Nrf2(-/-) cells, HO-1 gene activation increased gradually and HO-1 protein levels were approximately half of those attained in Nrf2(+/+) cells. The tyrosine kinase inhibitor genistein and JNK inhibitor SP600125 significantly attenuated arsenite induced increases in ho-1 mRNA levels in Nrf2 deficient cells but had negligible effects on Nrf2 activation, suggesting tyrosine kinase/JNK/c-Jun plays a key role in the HO-1 upregulation via AP-1.
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PMID:Differential roles for Nrf2 and AP-1 in upregulation of HO-1 expression by arsenite in murine embryonic fibroblasts. 1840 28

The chemopreventive and chemoprotective activities of green tea have been attributed to the polyphenolic ingredient (-)-epigallocatechin-3-gallate (EGCG). Here, we report that treatment of human breast epithelial (MCF10A) cells with EGCG induces the expression of glutamate-cysteine ligase, manganese superoxide dismutase (MnSOD), and heme oxygenase-1 (HO-1). NF-E2-related factor (Nrf2) has been reported to regulate the antioxidant response element (ARE)-mediated expression of many antioxidant as well as detoxifying enzymes. The nuclear accumulation, ARE binding and transcriptional activity of Nrf2 were increased by EGCG treatment. Silencing of Nrf2 by siRNA gene knockdown rendered the MCF10A cells less sensitive to the EGCG-induced expression of HO-1 and MnSOD. Furthermore, EGCG activated Akt and extracellular signal-regulated protein kinase1/2 (ERK1/2). The pharmacologic inhibition of these kinases abrogated the nuclear translocation of Nrf2 induced by EGCG. These findings suggest that Nrf2 mediates EGCG-induced expression of some representative antioxidant enzymes, possibly via Akt and ERK1/2 signaling, which may provide the cells with acquired antioxidant defense capacity to survive the oxidative stress.
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PMID:(-)-Epigallocatechin gallate induces Nrf2-mediated antioxidant enzyme expression via activation of PI3K and ERK in human mammary epithelial cells. 1842 57

The Nrf2/anti-oxidant response element (ARE) pathway plays an important role in regulating cellular anti-oxidants, including haem oxygenase-1 (HO-1). Various kinases have been implicated in the pathways leading to Nrf2 activation. Here, we investigated the effect of epigallocatechin (EGC) on ARE-mediated gene expression in human monocytic cells. EGC time and dose dependently increased HO-1 mRNA and protein expression but had minimal effect on expression of other ARE-regulated genes, including NAD(P)H:quinone oxidoreductase 1, glutathione cysteine ligase and ferritin. siRNA knock down of Nrf2 significantly inhibited EGC-induced HO-1 expression. Furthermore, inhibition of PKC by Ro-31-8220 dose dependently decreased EGC-induced HO-1 mRNA expression, whereas MAP kinase and phosphatidylinositol-3-kinase pathway inhibitors had no significant effect. EGC stimulated phosphorylation of PKCalphabeta and delta in THP-1 cells. PKCdelta inhibition significantly decreased EGC-induced HO-1 mRNA expression, whereas PKCalpha- and beta-specific inhibitors had no significant effect. These results demonstrate for the first time that EGC-induced HO-1 expression occurs via PKCdelta and Nrf2.
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PMID:Epigallocatechin activates haem oxygenase-1 expression via protein kinase Cdelta and Nrf2. 1858 7


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