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The Regulation of AP-1 Activity by Mitogen-Activated Protein Kinases [and Discussion]
Philosophical Transactions B
Abstract
AP-1 is a collection of dimeric sequence specific, DNA binding, transcriptional activators composed of Jun and Fos subunits. The composition, the level and the activity of AP-1 complexes are regulated in response to extracellular stimuli. An important role in this regulation is played by mitogen-activated protein kinases (MAPKs). The specific roles of three MAPKs, namely ERK, JNK and FRK, in modulation of both the level and activity of AP-1, are discussed.
... The AP-1 transcription factor complex, which is composed of members of the Jun (c-Jun, JunB, JunD), Fos (c-Fos, FosB, Fra1, Fra2), and activating TF (ATF) families, has emerged as a central player in cellular signaling, orchestrating various responses to oxidative and inflammatory stimuli [147,148]. Activation of AP-1, which is induced by prooxidant and proinflammatory triggers, influences cellular outcomes. Notably, AP-1's involvement in the induction of the mouse HO-1 gene underscores its role in stress-responsive gene expression, indicating its importance in cellular stress adaptation [113,149]. ...
... This interplay underscores the nuanced regulation of HO-1 expression, highlighting the cross-talk between various transcriptional regulators in the cellular response to PPARγ agonists. Sp1 and AP-1, which are transcription factors that are sensitive to oxidative stress and inflammatory signals, modulate HO-1 expression [147,148,150,151]. Sp1, which is a central mediator of cellular responses, responds to a plethora of signals, orchestrating a finely tuned regulatory network [141,142]. ...
... Our study showed the pivotal role of Sp1 in PPARγ agonist-induced HO-1 expression, offering a potential target for therapeutic interventions. Similarly, AP-1, which is composed of diverse family members, serves as a central player in cellular signaling, responding to oxidative and inflammatory stimuli [147,148,150]. Deciphering the interactions between AP-1 and PPARγ agonists provides insights into stress-responsive gene expression, paving the way for innovative strategies to mitigate oxidative stress-related disorders. ...
The activation of peroxisome proliferator-activated receptor (PPAR)-γ has been extensively shown to attenuate inflammatory responses in conditions such as asthma, acute lung injury, and acute respiratory distress syndrome, as demonstrated in animal studies. However, the precise molecular mechanisms underlying these inhibitory effects remain largely unknown. The upregulation of heme oxygenase-1 (HO-1) has been shown to confer protective effects, including antioxidant, antiapoptotic, and immunomodulatory effects in vitro and in vivo. PPARγ is highly expressed not only in adipose tissues but also in various other tissues, including the pulmonary system. Thiazolidinediones (TZDs) are highly selective agonists for PPARγ and are used as antihyperglycemic medications. These observations suggest that PPARγ agonists could modulate metabolism and inflammation. Several studies have indicated that PPARγ agonists may serve as potential therapeutic candidates in inflammation-related diseases by upregulating HO-1, which in turn modulates inflammatory responses. In the respiratory system, exposure to external insults triggers the expression of inflammatory molecules, such as cytokines, chemokines, adhesion molecules, matrix metalloproteinases, and reactive oxygen species, leading to the development of pulmonary inflammatory diseases. Previous studies have demonstrated that the upregulation of HO-1 protects tissues and cells from external insults, indicating that the induction of HO-1 by PPARγ agonists could exert protective effects by inhibiting inflammatory signaling pathways and attenuating the development of pulmonary inflammatory diseases. However, the mechanisms underlying TZD-induced HO-1 expression are not well understood. This review aimed to elucidate the molecular mechanisms through which PPARγ agonists induce the expression of HO-1 and explore how they protect against inflammatory and oxidative responses.
... In the AP-1 pathway, resveratrol inhibited TNF-induced stimulation of AP-1-mediated gene expression [45,54]. AP-1 is a transcription factor that controls various cellular processes such as proliferation, differentiation, apoptosis, and inflammation [55,56], and numerous extracellular stimuluses could activate it [55]. Although studies indicate the direct inhibitory action of resveratrol on COX-2 activity, the indirect impact of decreasing COX-2 expression after inhibiting AP-1 seems to be more significant [57]. ...
... In the AP-1 pathway, resveratrol inhibited TNF-induced stimulation of AP-1-mediated gene expression [45,54]. AP-1 is a transcription factor that controls various cellular processes such as proliferation, differentiation, apoptosis, and inflammation [55,56], and numerous extracellular stimuluses could activate it [55]. Although studies indicate the direct inhibitory action of resveratrol on COX-2 activity, the indirect impact of decreasing COX-2 expression after inhibiting AP-1 seems to be more significant [57]. ...
Background
The evidence for resveratrol's anti-obesity and anti-inflammatory qualities is accumulating, though meta-analyses have reported mixed results. The current umbrella meta-analysis aimed to assess the present evidence and provide an accurate estimate of the overall effects of resveratrol on the anthropometric indices and inflammatory markers.
Method
The Web of Science, PubMed, Scopus, and Google Scholar databases were searched till March 2023. The meta-analysis was performed utilizing a random-effects model. Moreover, the overall strength and quality of the evidence were assessed using the GRADE tool.
Results
The results from 19 meta-analyses investigating 81 unique randomized controlled trials with 4088 participants revealed that resveratrol supplementation reduced the body mass index (ES = − 0.119, 95% CI (− 0.192, − 0.047), p = 0.001), waist circumference (ES = − 0.405, 95% CI [− 0.664, − 0.147], p = 0.002), serum levels of C-reactive protein (ES = − 0.390, 95% CI [− 0.474, − 0.306], p < 0.001), and tumor necrosis factor-α (ES = − 0.455, 95% CI [− 0.592, − 0.318], p < 0.001) in comparison to the control group. The effects of resveratrol on body weight and Interleukin-6 levels of participants were not significant. However, resveratrol administration significantly decreased body weight in trials with intervention duration ≥ 12 weeks [ES = − 0.160, 95% CI (− 0.268, − 0.052)] and supplement dosage ≥ 500 mg/day [ES = − 0.130, 95% CI (− 0.238, − 0.022)].
Conclusion
The findings suggest the beneficial effects of resveratrol supplementation on reducing general and central obesity, as well as decreasing some inflammatory markers. Nevertheless, further high-quality research is required to prove these achievements and also evaluate resveratrol's effects on other inflammatory markers.
... The enhanced p38 MAPK phosphorylation level was also found to be associated with malignancy in distinct types of cancers such as non-small cell lung cancer [24], breast cancer [25], and head and neck squamous cell carcinomas [26]. It is reported that p38 modulates the activity of the transcription factor activator protein-1(AP-1), which is one of the most well-described nuclear targets of the MAPK cascades and important for cell proliferation to contribute to malignant transformation [27]. Another study demonstrated that the protein complex of MK2 and p38 phosphorylates cytoplasmic heat shock protein 27 (HSP27), which plays a role in regulating cell migration and invasion in thyroid cancer cells [28]. ...
Glioblastoma (GBM) is the most aggressive and lethal brain tumor in adults. This study aimed to investigate the functional significance of aryl hydrocarbon receptor nuclear translocator (ARNT) in the pathogenesis of GBM. Analysis of public datasets revealed ARNT is upregulated in GBM tissues compared to lower grade gliomas or normal brain tissues. Higher ARNT expression correlated with the mesenchymal subtype and poorer survival in GBM patients. Silencing ARNT using lentiviral shRNAs attenuated the proliferative, invasive, and stem-like capabilities of GBM cell lines, while ARNT overexpression enhanced these malignant phenotypes. Single-cell RNA sequencing uncovered that ARNT is highly expressed in a stem-like subpopulation and is involved in regulating glycolysis, hypoxia response, and stress pathways. Mechanistic studies found ARNT activates p38 mitogen-activated protein kinase (MAPK) signaling to promote chemoresistance in GBM cells. Disrupting the ARNT/p38α protein interaction via the ARNT PAS-A domain restored temozolomide sensitivity. Overall, this study demonstrates ARNT functions as an oncogenic driver in GBM pathogenesis and represents a promising therapeutic target.
... These metals or their derivatives are general components used in CNT synthesis, and all of these induce ROS/RNS formation (Vallyathan et al. 1992, Hirano et al. 2019. Also, redox-sensitive transcription factors such as AP-1 and NF-kB are activated by asbestos/ CNT exposure and can alter the expression of several genes involved in inflammation, proliferation, apoptosis and the carcinogenesis process (Karin and Marshall 1996). Several studies confirm the production of ROS by mitochondria, their localization, and the resulting damage in reaction to asbestos/CNT exposures. ...
... 60 Additionally, Glun2B is the dominant NMDAR subunit mediating extracellular signal-regulated kinase 1/2 cascade activity, which is known to regulate sleep-wake distribution and NREM sleep duration. 61 Mitogen-activated protein kinases phosphorylate core clock gene regulators [62][63][64][65][66][67] , and these pathways are affected in SYNGAP1, NLGN3, FMR1 and SCN2A deficient mice and rats [68][69][70][71] , which also present with sleep impairments. 22,70,72,73 Thus, inadequate GluN2B cellular signalling could in part contribute to the sleep alterations observed in Grin2b +/mutants. ...
Pathogenic mutations in GRIN2B are an important cause of severe neurodevelopmental disorders resulting in epilepsy, autism and intellectual disability. GRIN2B encodes the GluN2B subunit of N-methyl-D-aspartate receptors (NMDARs), which are ionotropic glutamate receptors critical for normal development of the nervous system and synaptic plasticity. Here, we characterized a novel GRIN2B heterozygous knockout rat model with 24-hour EEG recordings. We found rats heterozygous for the deletion ( Grin2b +/- ) had a higher incidence of spontaneous absence seizures than wild-type rats ( Grin2b +/+ ). Spike and wave discharges, the electrographic correlate of absences seizures, were longer in duration and displayed increased higher overall spectral power in Grin2b +/- animals than those in Grin2b +/+ . Heterozygous mutant rats also had abnormal sleep-wake brain state dynamics over the circadian cycle. Specifically, we identified a reduction in total rapid eye movement sleep and, altered distributions of non-rapid eye movement sleep and wake epochs, when compared to controls. This was accompanied by an increase in overall spectral power during non-rapid eye movement sleep in Grin2b +/- . The sleep-wake phenotypes were largely uncorrelated to the incidence of spike and wave discharges. We then tested the antiseizure efficacy of ethosuximide, a T-type voltage-gated calcium channel blocker used in the treatment of absence seizures, and memantine, a noncompetitive NMDAR antagonist currently explored as a mono or adjunctive treatment option in NMDAR related neurodevelopmental disorders. Ethosuximide reduced the number and duration of spike and wave discharges, while memantine did not affect the number of spike and wave discharges but reduced their duration. These results highlight two potential therapeutic options for GRIN2B related epilepsy. Our data shows the new rat GRIN2B haploinsufficiency model exhibits clinically relevant phenotypes. As such, it could prove crucial in deciphering underlying pathological mechanisms and developing new therapeutically translatable strategies for GRIN2B neurodevelopmental disorders.
... The enhanced p38 MAPK phosphorylation level was also found to be associated with malignancy in distinct types of cancers such as non-small cell lung cancer (24), breast cancer (25) and head and neck squamous cell carcinomas(26). It is reported that p38 modulates the activity of the transcription factor activator protein-1(AP-1), which is one of the most well described nuclear targets of the MAPK cascades and important for cell proliferation to contribute to malignant transformation (27). Another study demonstrated that the protein complex of MK2 and p38 phosphorylates cytoplasmic heat shock protein 27 (HSP27), which plays a role in regulating cell migration and invasion in thyroid cancer cells (28). ...
Glioblastoma (GBM) is the most aggressive and lethal brain tumor in adults. This study aimed to investigate the functional significance of aryl hydrocarbon receptor nuclear translocator (ARNT) in the pathogenesis of GBM. Analysis of public datasets revealed ARNT is upregulated in GBM tissues compared to lower grade gliomas or normal brain tissues. Higher ARNT expression correlated with the mesenchymal subtype and poorer survival in GBM patients. Silencing ARNT using lentiviral shRNAs attenuated the proliferative, invasive, and stem-like capabilities of GBM cell lines, while ARNT overexpression enhanced these malignant phenotypes. Single-cell RNA sequencing uncovered that ARNT is highly expressed in a stem-like subpopulation and is involved in regulating glycolysis, hypoxia response, and stress pathways. Mechanistic studies found ARNT activates p38 mitogen-activated protein kinase (MAPK) signaling to promote chemoresistance in GBM cells. Disrupting the ARNT/p38α protein interaction via the ARNT PAS-A domain restored temozolomide sensitivity. Overall, this study demonstrates ARNT functions as an oncogenic driver in GBM pathogenesis and represents a promising therapeutic target.
We conducted a genome-wide association study (GWAS) in a multiethnic cohort of 920 at-risk infants for retinopathy of prematurity (ROP), a major cause of childhood blindness, identifying 1 locus at genome-wide significance level (p < 5×10 ⁻⁸ ) and 9 with significance of p < 5×10 ⁻⁶ for ROP ≥ stage 3. The most significant locus, rs2058019, reached genome-wide significance within the full multiethnic cohort (p = 4.96×10 ⁻⁹ ); Hispanic and European Ancestry infants driving the association. The lead single nucleotide polymorphism (SNP) falls in an intronic region within the Glioma-associated oncogene family zinc finger 3 ( GLI3 ) gene. Relevance for GLI3 and other top-associated genes to human ocular disease was substantiated through in-silico extension analyses, genetic risk score analysis and expression profiling in human donor eye tissues. Thus, we identify a novel locus at GLI3 with relevance to retinal biology, supporting genetic susceptibilities for ROP risk with possible variability by race and ethnicity.
The study aimed to explore the key targets and molecular mechanisms of Dahuang-Tusizi drug pair (DTDP) in the treatment of diabetes nephropathy (DN) based on the GEO database by using network pharmacology combined with molecular docking and immune infiltration. The active components of the DTDP were screened using the Traditional Chinese Medicine Systems Pharmacology database and the Swiss Target Prediction database. The differential genes of DN were retrieved from GEO databases. Next, the intersecting targets of drug and disease were imported into the String database for protein–protein interactions network analysis, and the core targets were identified through topological analysis. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed with the help of the Metascape database and gene set enrichment analysis database. Subsequently, molecular docking was performed to verify the binding activity of the key component and the key target. The Nephroseq V5 database was used to verify the clinical relevance of DN and core genes. Finally, the Using CIBERSORT Algorithm to analyze the immune Infiltration of DN Gene Chip. The network analysis showed that 25 active ingredients of DTDP were associated with 22 targets in DN. The key active ingredients (Sesamin, quercetin, EUPATIN, matrine, beta-sitosterol, isorhamnetin, etc.) and the core targets (JUN, EGF, CD44, FOS, KDR, CCL2, PTGS2, and MMP2) were further identified. Enrichment analysis revealed signaling pathways including TNF, MAPK, and IL-17 signaling pathway. Molecular docking results showed that there was a strong affinity between the key components and core targets. The results of immune infiltration found that the proportion of macrophages in DN tissues was significantly increased. Our findings demonstrated that the characteristics of DTDP in treating DN are “multiple components, multiple targets and multiple pathways.” We predicted that DTDP may inhibit inflammation related pathways by regulating key genes, reducing macrophage infiltration. Thus, inhibiting inflammatory response to reduce glomerular damage and delay the development of DN.
Mitogen-activated protein (MAP) kinases, also known as extracellular signal-regulated kinases (ERKs), are thought to act at
an integration point for multiple biochemical signals because they are activated by a wide variety of extracellular signals,
rapidly phosphorylated on threonine and tyrosine, and highly conserved. A critical protein kinase lies upstream of MAP kinase
and stimulates the enzymatic activity of MAP kinase. The structure of this protein kinase, denoted MEK1, for MAP kinase or
ERK kinase, was elucidated from a complementary DNA sequence and shown to be a protein of 393 amino acids (43,500 daltons)
that is related most closely in size and sequence to the product encoded by the Schizosaccharomyces pombe byr1 gene. The MEK
gene was highly expressed in murine brain, and the product expressed in bacteria phosphorylated the ERK gene product.
The ATF‐2 transcription factor can mediate adenovirus E1A‐inducible transcriptional activation. Deletion analysis has indicated that the N‐terminal region of ATF‐2 is essential for this response. Furthermore, the N‐terminus can activate transcription in the absence of E1A when fused to a heterologous DNA binding domain. However, in the intact protein this activation domain is masked. In this report we show that residues in the N‐terminus required for activation are also required for mediating E1A stimulation. In particular two threonine residues at positions 69 and 71 are essential. These residues are phosphorylated in vivo and can be efficiently phosphorylated in vitro by the JNK/SAPK subgroup of the MAPK family. ATF‐2 can bind to a UV‐inducible kinase through a region in the N‐terminus that is distinct from the sites of phosphorylation; this binding region is both necessary for phosphorylation by JNK/SAPK in vitro and for transcriptional activation in vivo. The activity of the N‐terminus is stimulated by UV irradiation which stimulates the signalling pathway leading to JNK/SAPK. Finally, although ATF‐2 binds to the E1A protein, the N‐terminal activation domain is not required for this interaction. The results show that ATF‐2, like other members of the ATF/CREB family of DNA binding proteins is regulated by specific signalling pathways.
THE retinoblastoma susceptibility gene product (pRb) plays an important role in constraining cellular proliferation and in regulating the cell cycle1,2. The pRb inhibits transcription of genes involved in growth control (reviewed in ref. 3) and can regulate transforming growth factor beta1 (TGF-beta1) gene expression4,5. TGF-beta isoforms also down-regulate cellular proliferation6,7. To determine whether pRb also regulates expression of other TGF-beta isoforms, we examined the effect of pRb on the expression of the human TGF-beta2 gene. The human TGF-beta2 promoter contains multiple elements including an ATF site, which is essential for basal promoter activity8. Here we report that pRb activates transcription of the human TGF-beta2 gene. The promoter element responsible for pRb-mediated transcriptional regulation is a binding site for ATF proteins, an extensive transcription factor family9. We provide evidence that implicates ATF-2 in pRb-responsiveness. First, the ATF promoter element in the TGF-beta2 gene is a high-affinity ATF-2-binding site. Second, a GAL4-ATF2 fusion protein can support pRb-mediated transcriptional activation of a promoter containing GAL4-binding sites. Third, ATF-2 in nuclear extracts can interact with pRb. Our results reveal a new mechanism by which pRb constrains cellular proliferation: by activating expression of the inhibitory growth factor, TGF-beta2.
Treatment of PC12 cells with nerve growth factor (NGF) induces a rapid increase in tyrosine phosphorylation of multiple cellular proteins. Expression of a dominant inhibitory Ras mutant specifically blocked NGF- and TPA-induced tyrosine phosphorylation of two proteins of approximately 42 and 44 kd. Conversely, expression of an oncogenic variant of Ras induced tyrosine phosphorylation of the same 42 and 44 kd proteins. The 44 kd protein was immunoprecipitated with an antibody directed against extracellular signal-regulated kinase 1/mitogen-activated protein kinase (MAPK) and the 42 kd protein comigrated with a 42 kd MAPK, indicating that at least one and probably both Ras-regulated phosphoproteins are MAPKs. In addition, MAPK activation, as measured by in vitro phosphorylation of myelin basic protein, was also regulated by Ras. Ras was not required for NGF-induced activation of Trk or tyrosine phosphorylation of PLC-gamma 1. Thus, NGF-induced tyrosine phosphorylation occurs both prior to and following Ras action, and Ras plays a critical role in the NGF- and TPA-induced tyrosine phosphorylation of MAPKs.
Transcription of the proto-oncogene c-fos is stimulated rapidly and transiently by serum growth factors and mitogens. Critical for this response is the serum-response element which is bound in vivo in a ternary complex containing the transcription factors p67SRF and p62TCF (ref. 2). Disruption of the ternary complex correlates with impaired induction by serum and phorbol ester. Mitogen-activated protein (MAP) kinase is a serine/threonine kinase which is activated 1-5 minutes after treatment of cells with mitogens and growth factors that induce re-entry into the cell cycle, making MAP kinase a candidate for the transmission of proliferative signals. Here we show that p62TCF is phosphorylated by MAP kinase in vitro and that phosphorylation results in enhanced ternary complex formation. Serum-starved Swiss 3T3 cells treated with epidermal growth factor, which induces MAP kinase in these cells, are induced to express c-fos and yield p62TCF active in ternary complex formation. In contrast, treatment of Swiss 3T3 cells with insulin, which does not activate MAP kinase under these conditions, does not lead to enhanced ternary complex formation nor does it induce c-fos transcription. Our results link the expression of the human c-fos proto-oncogene to signal transduction pathways known to be activated before its own induction.
Mitogen-activated protein (MAP) kinases are 42- and 44-kD serine-threonine protein kinases that are activated by tyrosine
and threonine phosphorylation in cells stimulated with mitogens and growth factors. MAP kinase and the protein kinase that
activates it (MAP kinase kinase) were constitutively activated in NIH 3T3 cells infected with viruses containing either of
two oncogenic forms (p35EC12, p3722W) of the c-Raf-1 protein kinase. The v-Raf proteins purified from cells infected with
EC12 or 22W viruses activated MAP kinase kinase from skeletal muscle in vitro. Furthermore, a bacterially expressed v-Raf
fusion protein (glutathione S-transferase-p3722W) also activated MAP kinase kinase in vitro. These findings suggest that one
function of c-Raf-1 in mitogenic signaling is to phosphorylate and activate MAP kinase kinase.
Here we demonstrate that partially purified Xenopus p42 mitogen-activated protein (MAP) kinase phosphorylates bacterially expressed human c-Jun at a single site, serine 243. Several lines of evidence argue that this phosphorylation is due to p42 MAP kinase itself rather than some contaminating species. Phosphorylation of serine 243 markedly decreases the binding of c-Jun to oligonucleotides containing the 12-O-tetradecanoylphorbol-13-acetate response element. These findings suggest that MAP kinase may play a role in the down-regulation of c-Jun or in the cycle of transcriptional initiation and elongation.
The promoters of many genes whose transcription is rapidly and transiently induced following growth factor or mitogen stimulation of susceptible cells contain a common regulatory element, the serum response element (SRE). As the transcription factors that bind the SRE and the signalling molecules that affect its activity are characterized in more detail, the major challenge is to elucidate the signalling pathways that link cell-surface receptors to the SRE, and to determine the mechanism by which signalling events modulate transcription factor activity.
Exposure of mammalian cells to DNA-damaging agents induces the ultraviolet (UV) response, involving transcription factor AP-1, composed of Jun and Fos proteins. We investigated the mechanism by which UV irradiation induces the c-jun gene. The earliest detectable step was activation of Src tyrosine kinases, followed by activation of Ha-Ras and Raf-1. The response to UV was blocked by tyrosine kinase inhibitors and dominant negative mutants of v-src, Ha-ras, and raf-1. This signaling cascade leads to increased phosphorylation of c-Jun on two serine residues that potentiate its activity. These results strongly suggest that the UV response is initiated at or near the plasma membrane rather than the nucleus. The response may be elicited by oxidative stress, because it is inhibited by elevation of intracellular glutathione. Using tyrosine kinase inhibitors, we demonstrate that the UV response has a protective function.