Mitogen-Activated Protein Kinase Pathways Mediated by ERK, JNK, and p38 Protein Kinases

Johnson, Gary L.; Lapadat, Razvan

doi:10.1126/science.1072682

Cited by 3,783 publications

(2,750 citation statements)

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“…The types of known MAPKs are extracellular signal-regulated kinase 1 and 2 (ERK 1/2), ERK 5, JNK 1–3, and p38 protein isoforms (p38α, β, γ, and δ) [153]. Among the MAPKs, p38 MAPKs regulate the expression of many cytokines [154]. …”

Section: Mechanisms Of Action In Disease Preventionmentioning

confidence: 99%

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Anthocyanidins and anthocyanins: colored pigments as food, pharmaceutical ingredients, and the potential health benefits

Khoo

Azlan

Tang

et al. 2017

Food & Nutrition Research

2,068

1,327

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Anthocyanins are colored water-soluble pigments belonging to the phenolic group. The pigments are in glycosylated forms. Anthocyanins responsible for the colors, red, purple, and blue, are in fruits and vegetables. Berries, currants, grapes, and some tropical fruits have high anthocyanins content. Red to purplish blue-colored leafy vegetables, grains, roots, and tubers are the edible vegetables that contain a high level of anthocyanins. Among the anthocyanin pigments, cyanidin-3-glucoside is the major anthocyanin found in most of the plants. The colored anthocyanin pigments have been traditionally used as a natural food colorant. The color and stability of these pigments are influenced by pH, light, temperature, and structure. In acidic condition, anthocyanins appear as red but turn blue when the pH increases. Chromatography has been largely applied in extraction, separation, and quantification of anthocyanins. Besides the use of anthocyanidins and anthocyanins as natural dyes, these colored pigments are potential pharmaceutical ingredients that give various beneficial health effects. Scientific studies, such as cell culture studies, animal models, and human clinical trials, show that anthocyanidins and anthocyanins possess antioxidative and antimicrobial activities, improve visual and neurological health, and protect against various non-communicable diseases. These studies confer the health effects of anthocyanidins and anthocyanins, which are due to their potent antioxidant properties. Different mechanisms and pathways are involved in the protective effects, including free-radical scavenging pathway, cyclooxygenase pathway, mitogen-activated protein kinase pathway, and inflammatory cytokines signaling. Therefore, this review focuses on the role of anthocyanidins and anthocyanins as natural food colorants and their nutraceutical properties for health. Abbreviations: CVD: Cardiovascular disease VEGF: Vascular endothelial growth factor

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Section: Mechanisms Of Action In Disease Preventionmentioning

confidence: 99%

“…During the inflammation process, these cytokines activate hypothalamic-pituitary-adrenal that acts on the release of glucocorticoids from the adrenal cortex. The inflammatory cytokine IL-1 also activates p38 MAPKs during the inflammatory process [154]. …”

Section: Mechanisms Of Action In Disease Preventionmentioning

confidence: 99%

Anthocyanidins and anthocyanins: colored pigments as food, pharmaceutical ingredients, and the potential health benefits

Khoo

Azlan

Tang

et al. 2017

Food & Nutrition Research

2,068

1,327

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“…The recent discovery of these mutations not only resulted in better understanding of melanoma and its progression but also resulted in advancement of targeted therapies 22, 3, 4…”

Section: Introductionmentioning

confidence: 99%

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

Yamazaki¹,

Tsutsumida²,

Takahashi³

et al. 2018

The Journal of Dermatology

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The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (PK) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (AE), and the primary end‐point in phase 2 was to assess confirmed overall response rate (ORR). The secondary end‐points in phase 1 included PK, confirmed/unconfirmed ORR and duration of response (DOR). The secondary end‐points in phase 2 were PK, unconfirmed ORR, DOR, safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common AE (≥50.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator‐assessed ORR was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9–99.6; P < 0.0001) in phase 2. Plasma concentrations of both dabrafenib and trametinib seemed to a reach steady state by week 3. Overall, efficacy and PK properties for the dabrafenib plus trametinib combination in Japanese patients were comparable with those seen in global studies.

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“…Cell cycle progression is regulated by Erk (extracellular signal regulated) kinase, a member of the mitogen-activated protein kinase family (Kolch, 2000;Johnson and Lapadat, 2002). Erk is activated by its upstream kinases, MEK1 and MEK2 (Krepinsky et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

ERK activity facilitates activation of the S-phase DNA damage checkpoint by modulating ATR function

Chen

Parihar

et al. 2005

Oncogene

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Although Erk kinase has been recently reported to function in the DNA damage response, the mechanism governing this process is unknown. We report here that hydroxyurea (HU) activates Erk via MEK1, a process that is sensitized by a constitutively active MEK1 (MEK1Q56P) and attenuated by a dominant-negative MEK1 (MEK1K97M). While ectopic MEK1Q56P sensitized HU-induced S-phase arrest, inhibition of Erk activation via U0126, PD98059, and MEK1K97M attenuated the arrest, and thereby enhanced cells to HU-induced toxicity. Taken together, we demonstrate an important contribution of Erk to the activation of the S-phase DNA damage checkpoint. This can be attributed to Erk's regulatory role in modulating ATR function. Inhibition of Erk activation with U0126/PD98059 and MEK1K97M substantially reduced HU-induced ATR nuclear foci, leading to a dramatic reduction of cH2AX and its nuclear foci. Reduction of MEK1 function by a small interference RNA (siRNA) MEK1 and ectopic MEK1K97M significantly decreased HU-induced cH2AX. Conversely, ectopic MEK1Q56P enhanced cH2AX foci. Furthermore, immunofluorescent and cell fractioning experiments revealed cytosolic and nuclear localization of ATR. HU treatment caused the redistribution of ATR from the cytosol to the nucleus, a process that is inhibited by U0126. Collectively, we show that Erk kinase modulates HU-initiated DNA damage response by regulating ATR function.

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Mitogen-Activated Protein Kinase Pathways Mediated by ERK, JNK, and p38 Protein Kinases

Cited by 3,783 publications

References 10 publications

Anthocyanidins and anthocyanins: colored pigments as food, pharmaceutical ingredients, and the potential health benefits

Anthocyanidins and anthocyanins: colored pigments as food, pharmaceutical ingredients, and the potential health benefits

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

ERK activity facilitates activation of the S-phase DNA damage checkpoint by modulating ATR function

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