Stress-activated Protein Kinase Research Articles

Drosophila Toll-9 is induced by aging and neurodegeneration to modulate stress signaling and its deficiency exacerbates tau-mediated neurodegeneration

Drosophila Toll-9 is most closely related to mammalian Toll-like receptors; however, physiological functions of Toll-9 remain elusive. We examined the roles of Toll-9 in fly brains in aging and neurodegeneration. Toll-9 mRNA levels were increased in aged fly heads accompanied by activation of nuclear factor-kappa B (NF-kB) and stress-activated protein kinase (SAPK) signaling, and many of these changes were modulated by Toll-9 in glial cells. The loss of Toll-9 did not affect lifespan or brain integrity, whereas it exacerbated hydrogen peroxide-induced lethality. Toll-9 expression was also induced by nerve injury but did not affect acute stress response or glial engulfment activity, suggesting Toll-9 may modulate subsequent neurodegeneration. In a fly tauopathy model, Toll-9 deficiency enhanced neurodegeneration and disease-related tau phosphorylation with reduced SAPK activity, and blocking SAPK enhanced tau phosphorylation and neurodegeneration. In sum, Toll-9 is induced upon aging and nerve injury and affects neurodegeneration by modulating stress kinase signaling.

Perturbed fatty-acid metabolism is linked to localized chromatin hyperacetylation, increased stress-response gene expression and resistance to oxidative stress.

Oxidative stress is associated with cardiovascular and neurodegenerative diseases, diabetes, cancer, psychiatric disorders and aging. In order to counteract, eliminate and/or adapt to the sources of stress, cells possess elaborate stress-response mechanisms, which also operate at the level of regulating transcription. Interestingly, it is becoming apparent that the metabolic state of the cell and certain metabolites can directly control the epigenetic information and gene expression. In the fission yeast Schizosaccharomyces pombe, the conserved Sty1 stress-activated protein kinase cascade is the main pathway responding to most types of stresses, and regulates the transcription of hundreds of genes via the Atf1 transcription factor. Here we report that fission yeast cells defective in fatty acid synthesis (cbf11, mga2 and ACC/cut6 mutants; FAS inhibition) show increased expression of a subset of stress-response genes. This altered gene expression depends on Sty1-Atf1, the Pap1 transcription factor, and the Gcn5 and Mst1 histone acetyltransferases, is associated with increased acetylation of histone H3 at lysine 9 in the corresponding gene promoters, and results in increased cellular resistance to oxidative stress. We propose that changes in lipid metabolism can regulate the chromatin and transcription of specific stress-response genes, which in turn might help cells to maintain redox homeostasis.

The regulatory mechanism of the yeast osmoresponse under different glucose concentrations

Cells constantly respond to environmental changes by modulating gene expression programs. These responses may demand substantial costs and, thus, affect cell growth. Understanding the regulation of these processes represents a key question in biology and biotechnology. Here, we studied the responses to osmotic stress in glucose-limited environments. By analyzing seventeen osmotic stress-induced genes and stress-activated protein kinase Hog1, we found that cells exhibited stronger osmotic gene expression response and larger integral of Hog1 nuclear localization during adaptation to osmotic stress under glucose-limited conditions than under glucose-rich conditions. We proposed and verified that in glucose-limited environment, glycolysis intermediates (representing "reserve flux") were limited, which required cells to express more glycerol-production enzymes for stress adaptation. Consequently, the regulatory mechanism of osmoresponse was derived in the presence and absence of such reserve flux. Further experiments suggested that this reserve flux-dependent stress-defense strategy may be a general principle under nutrient-limited environments.

Leptospiral lipopolysaccharide mediated Hog1 phosphorylation in Saccharomyces cerevisiae directs activation of autophagy

Cells have developed a variety of mechanisms to counteract stress to give a specific and adaptive response. Yeast Hog1 is a homolog to mammalian p38, which is a mitogen-activated protein kinase. In this work, we analyze the Hog1 signaling during the induction of leptospiral LPS (100 ng/mL) and the hyperosmotic element NaCl (0.8 M). After the addition of stress elements, the stress-activated protein kinase was phosphorylated within 30 min of exposure and led to the expression of various genes responsible for cell survival. We found that leptospiral lipopolysaccharide mediated Hog1 phosphorylation leads to activation of autophagy-related genes phosphorylation; thereby cells encounter and digest the metabolic waste or organelles for their energy during starvation. And, the wild-type cells accumulate lipid droplets and trigger vacuole calcium release, to maintain cell survival. Loss of Hog1 leads to shrinkage in the cell wall, condensation of the cytoplasmic part, and high-level ROS production. This led to the Hog1 mutant cell death under LPS treatment or stress condition. The phosphorylation of stress-activated kinase during exposure to leptospiral LPS provides insight and knowledge about the organization of cellular metabolic products and cell survival during stress conditions and identifies the pathogenic mechanisms of leptospirosis.

Mitogen-activated protein kinase kinase 7 in inflammatory, cancer, and neurological diseases.

Stress-activated mitogen-activated protein kinase kinase 7 (MKK7) is a member of the dual-specificity mitogen-activated protein kinase family. In the human body, MKK7 controls essential physiological processes, including but not limited to proliferation and differentiation in multiple tissues and organs. MKK7, along with the MKK4 pathway, has been implicated in stress-activated activities and biological events that are mediated by c-Jun N-terminal kinase (JNK) signaling. Although numerous studies have been performed to identify the role of JNK in multiple biological processes, there are limited publications that focus on dissecting the independent role of MKK7. Recent research findings have spurred testing via in vivo genetically deficient models, uncovering previously undocumented JNK-independent functions of MKK7. Here we discuss both JNK-dependent and-independent functions of MKK7 in vivo. This review summarizes the role of MKK7 in inflammation, cytokine production, cancer, and neurological diseases.

CAMP-Protein kinase A and stress-activated MAP kinase signaling mediate transcriptional control of autophagy in fission yeast during glucose limitation or starvation

ABSTRACT Macroautophagy/autophagy is an essential adaptive physiological response in eukaryotes induced during nutrient starvation, including glucose, the primary immediate carbon and energy source for most cells. Although the molecular mechanisms that induce autophagy during glucose starvation have been extensively explored in the budding yeast Saccharomyces cerevisiae, little is known about how this coping response is regulated in the evolutionary distant fission yeast Schizosaccharomyces pombe. Here, we show that S. pombe autophagy in response to glucose limitation relies on mitochondrial respiration and the electron transport chain (ETC), but, in contrast to S. cerevisiae, the AMP-activated protein kinase (AMPK) and DNA damage response pathway components do not modulate fission yeast autophagic flux under these conditions. In the presence of glucose, the cAMP-protein kinase A (PKA) signaling pathway constitutively represses S. pombe autophagy by downregulating the transcription factor Rst2, which promotes the expression of respiratory genes required for autophagy induction under limited glucose availability. Furthermore, the stress-activated protein kinase (SAPK) signaling pathway, and its central mitogen-activated protein kinase (MAPK) Sty1, positively modulate autophagy upon glucose limitation at the transcriptional level through its downstream effector Atf1 and by direct in vivo phosphorylation of Rst2 at S292. Thus, our data indicate that the signaling pathways that govern autophagy during glucose shortage or starvation have evolved differently in S. pombe and uncover the existence of sophisticated and multifaceted mechanisms that control this self-preservation and survival response.

Time and age dependent regulation of neuroinflammation in a rat model of mesial temporal lobe epilepsy: Correlation with human data.

Acute brain insults trigger diverse cellular and signaling responses and often precipitate epilepsy. The cellular, molecular and signaling events relevant to the emergence of the epileptic brain, however, remain poorly understood. These multiplex structural and functional alterations tend also to be opposing - some homeostatic and reparative while others disruptive; some associated with growth and proliferation while others, with cell death. To differentiate pathological from protective consequences, we compared seizure-induced changes in gene expression hours and days following kainic acid (KA)-induced status epilepticus (SE) in postnatal day (P) 30 and P15 rats by capitalizing on age-dependent differential physiologic responses to KA-SE; only mature rats, not immature rats, have been shown to develop spontaneous recurrent seizures after KA-SE. To correlate gene expression profiles in epileptic rats with epilepsy patients and demonstrate the clinical relevance of our findings, we performed gene analysis on four patient samples obtained from temporal lobectomy and compared to four control brains from NICHD Brain Bank. Pro-inflammatory gene expressions were at higher magnitudes and more sustained in P30. The inflammatory response was driven by the cytokines IL-1β, IL-6, and IL-18 in the acute period up to 72 h and by IL-18 in the subacute period through the 10-day time point. In addition, a panoply of other immune system genes was upregulated, including chemokines, glia markers and adhesion molecules. Genes associated with the mitogen activated protein kinase (MAPK) pathways comprised the largest functional group identified. Through the integration of multiple ontological databases, we analyzed genes belonging to 13 separate pathways linked to Classical MAPK ERK, as well as stress activated protein kinases (SAPKs) p38 and JNK. Interestingly, genes belonging to the Classical MAPK pathways were mostly transiently activated within the first 24 h, while genes in the SAPK pathways had divergent time courses of expression, showing sustained activation only in P30. Genes in P30 also had different regulatory functions than in P15: P30 animals showed marked increases in positive regulators of transcription, of signaling pathways as well as of MAPKKK cascades. Many of the same inflammation-related genes as in epileptic rats were significantly upregulated in human hippocampus, higher than in lateral temporal neocortex. They included glia-associated genes, cytokines, chemokines and adhesion molecules and MAPK pathway genes. Uniquely expressed in human hippocampus were adaptive immune system genes including immune receptors CDs and MHC II HLAs. In the brain, many immune molecules have additional roles in synaptic plasticity and the promotion of neurite outgrowth. We propose that persistent changes in inflammatory gene expression after SE leads not only to structural damage but also to aberrant synaptogenesis that may lead to epileptogenesis. Furthermore, the sustained pattern of inflammatory genes upregulated in the epileptic mature brain was distinct from that of the immature brain that show transient changes and are resistant to cell death and neuropathologic changes. Our data suggest that the epileptogenic process may be a result of failed cellular signaling mechanisms, where insults overwhelm the system beyond a homeostatic threshold.

Regulation of Stress-Activated Kinases in Response to Tacaribe Virus Infection and Its Implications for Viral Replication.

Arenaviruses include important zoonotic pathogens that cause hemorrhagic fever (e.g., Junín virus; JUNV) as well as other viruses that are closely related but apathogenic (e.g., Tacaribe virus; TCRV). We have found that, while TCRV and JUNV differ in their ability to induce apoptosis in infected cells, due to active inhibition of caspase activation by the JUNV nucleoprotein, both viruses trigger similar upstream pro-apoptotic signaling events, including the activation/phosphorylation of p53. In the case of TCRV, the pro-apoptotic factor Bad is also phosphorylated (leading to its inactivation). These events clearly implicate upstream kinases in regulating the induction of apoptosis. Consistent with this, here we show activation in TCRV-infected cells of the stress-activated protein kinases p38 and JNK, which are known to regulate p53 activation, as well as the downstream kinase MK2 and transcription factor c-Jun. We also observed the early transient activation of Akt, but not Erk. Importantly, the chemical inhibition of Akt, p38, JNK and c-Jun all dramatically reduced viral growth, even though we have shown that inhibition of apoptosis itself does not. This indicates that kinase activation is crucial for viral infection, independent of its downstream role in apoptosis regulation, a finding that has the potential to shed further light on the determinants of arenavirus pathogenesis, as well as to inform future therapeutic approaches.

Regulation of Claspin by the p38 stress-activated protein kinase protects cells from DNA damage.

Stress-activated protein kinases (SAPKs) enhance survival in response to environmental changes. In yeast, the Hog1 SAPK and Mrc1, a protein required for DNA replication, define a safeguard mechanism that allows eukaryotic cells to prevent genomic instability upon stress during S-phase. Here we show that, in mammals, the p38 SAPK and Claspin-the functional homolog of Mrc1-protect cells from DNA damage upon osmostress during S-phase. We demonstrate that p38 phosphorylates Claspin and either the mutation of the p38-phosphorylation sites in Claspin or p38 inhibition suppresses the protective role of Claspin on DNA damage. In addition, wild-type Claspin but not the p38-unphosphorylatable mutant has a protective effect on cell survival in response to cisplatin treatment. These findings reveal a role of Claspin in response to chemotherapeutic drugs. Thus, this pathway protects S-phase integrity from different insults and it is conserved from yeast to mammals.

Mechanism of Shaofu Zhuyu Decoction in treatment of endometriosis-associated dysmenorrhea with syndrome of cold coagulation and blood stasis based on MSK1/2

This study aims to decipher the mechanism underlying the effect of Shaofu Zhuyu Decoction on endometriosis(EMT)-associated dysmenorrhea in rats with the syndrome of cold coagulation and blood stasis based on mitogen-and stress-activated protein kinase 1/2(MSK1/2).We employed a random number table to randomly assign SPF female non-pregnant rats into the sham group, and treated the rest rats with autologous transplantation+refrigerator freezing for the modeling of the syndrome of cold coagulation and blood stasis.The modeled rats were then randomly assigned into the control group and high-, medium-and low-dose Shaofu Zhuyu Decoction groups.The rats in the low-, medium-, and high-dose decoction groups were respectively administrated with 9, 4.5, and 2.3 g·kg~(-1) decoction through gavage once a day for 2 consecutive weeks, and those in the control group were administrated with 0.24 mg·kg~(-1) gestrinone through gavage once every 3 days for 2 weeks.After that, the size of ectopic focus in each rat was measured via laparotomy.Enzyme-linked immunosorbent assay(ELISA) was adopted to determine the expression of interleukin(IL)-6, IL-10, prostaglandin E2(PGE2), tumor necrosis factor-α(TNF-α).Western blot was employed to determine the protein levels of MSK1/2 and dual-specificity phosphatase 1(DUSP1) and real-time quantitative polymerase chain reaction(RT-PCR) to determine the mRNA levels of the two genes in rat eutopic endometrial tissue.Compared with the sham group, the model group showed increased levels of IL-6, PGE2, and TNF-α while decrease level of IL-10 in the serum(P<0.01).Compared with the model group, the high-and medium-dose decoction groups and the gestrinone group had declined levels of IL-6, PGE2, and TNF-α while risen level of IL-10 in the serum(P<0.01).The model group had lower protein levels and mRNA levels of MSK1/2 and DUSP1 in the eutopic endometrial tissue than the sham group(P<0.01). The high-and medium-dose decoction groups and the gestrinone group had higher protein and mRNA levels of MSK1/2 and DUSP1 in the eutopic endometrial tissue than the model group(P<0.01).The results indicated that Shaofu Zhuyu Decoction can regulate the abnormal expression of pro-inflammatory cytokines TNF-α, IL-6, and PGE2 and anti-inflammatory cytokines IL-10 and DUSP1 via MSK1/2 to alleviate EMT-associated dysmenorrhea in rats with the syndrome of cold coagulation and blood stasis.

The Developmental Transcription Factor p63 Is Redeployed to Drive Allergic Skin Inflammation through Phosphorylation by p38α.

Keratinocytes, the epithelial cells of the skin, reprogram their gene expression and produce immune effector molecules when exposed to environmental and endogenous triggers of inflammation. It remains unclear how keratinocytes process physiological signals generated during skin irritation and switch from a homeostatic to an inflammatory state. In this article, we show that the stress-activated protein kinase p38α is crucial for keratinocytes to prompt changes in their transcriptome upon cytokine stimulation and drive inflammation in allergen-exposed skin. p38α serves this function by phosphorylating p63, a transcription factor essential for the lineage identity and stemness of the skin epithelium. Phosphorylation by p38α alters the activity of p63 and redeploys this developmental transcription factor to a gene expression program linked to inflammation. Genetic ablation and pharmacological inhibition of p38α or the p38α-p63 target gene product MMP13 attenuate atopic dermatitis-like disease in mice. Our study reveals an epithelial molecular pathway promoting skin inflammation and actionable through treatment with topical small-molecule therapeutics.

Hyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses

Soluble aggregates of the microtubule-associated protein tau have been challenging to assemble and characterize, despite their important role in the development of tauopathies. We found that sequential hyperphosphorylation by protein kinase A in conjugation with either glycogen synthase kinase 3β or stress activated protein kinase 4 enabled recombinant wild-type tau of isoform 0N4R to spontaneously polymerize into small amorphous aggregates in vitro. We employed tandem mass spectrometry to determine the phosphorylation sites, high-resolution native mass spectrometry to measure the degree of phosphorylation, and super-resolution microscopy and electron microscopy to characterize the morphology of aggregates formed. Functionally, compared with the unmodified aggregates, which require heparin induction to assemble, these self-assembled hyperphosphorylated tau aggregates more efficiently disrupt membrane bilayers and induce Toll-like receptor 4-dependent responses in human macrophages. Together, our results demonstrate that hyperphosphorylated tau aggregates are potentially damaging to cells, suggesting a mechanism for how hyperphosphorylation could drive neuroinflammation in tauopathies.

Regulation of Mitogen‐Activated Protein Kinase Hog1 Phosphorylation Induced by DNA Damage Agent in Saccharomyces cerevisiae

DNA damage is a harmful and unavoidable stress frequently encountered by living organisms. It is crucial for organisms to have elaborated mechanisms in response to DNA damage, and a thorough understanding of these mechanisms and their regulation is very important. Hog1 is a stress‐activated protein kinase in Saccharomyces cerevisiae, which responds to osmolarity changes as well as various other stressors. Recently, we found that Hog1 can be activated by DNA damage agent, and the activation is primarily mediated by the Sln1 branch of the HOG pathway. Interestingly, we observed that DNA damage agent‐induced activation of Hog1 is substantially elevated when treated with cycloheximide, a protein synthesis inhibitor, suggesting the existence of a mechanism that keeps the extent of Hog1 activation in check. Notably, the cycloheximide effect is diminished in several phosphatase deletion mutants, suggesting a profound involvement of phosphatase in this process. The detailed characterization of the role of phosphatase in regulating DNA damage‐induced Hog1 activation is currently underway.

Hsp90 and phosphorylation of the Slt2(Mpk1) MAP kinase activation loop are essential for catalytic, but not non-catalytic, Slt2-mediated transcription in yeast

In yeast, the Slt2(Mpk1) stress-activated protein kinase directs the activation of two transcription factors, Rlm1 and Swi4/Swi6, in response to cell wall stress. Rlm1 is activated through a phosphorylation by Slt2, whereas the Swi4/Swi6 activation is noncatalytic and triggered by the binding of phosphorylated forms of both Slt2 and a catalytically inactive pseudokinase (Mlp1). Previous studies have delineated a role for the molecular chaperone Hsp90 in the activation of Slt2, but the involvement of Hsp90 in these events of catalytic versus non-catalytic cell integrity signaling has remained elusive. In cells lacking Mlp1, the Hsp90 inhibitor radicicol was found to inhibit the Slt2-mediated catalytic activation of Rlm1, but not the noncatalytic activation of Swi4/Swi6. Mutation of residues in the TEY motif of the Slt2 activation loop strongly impacted both Hsp90 binding and Rlm1-mediated transcription. In contrast, many of these same mutations had only modest effects on Swi4/6 (Slt2-mediated, non-catalytic) transcription, although one that blocked both the Slt2:Hsp90 interaction and Rlm1-mediated transcription (E191G) triggered a hyperactivation of Swi4/6. Taken together, our results cement the importance of the Slt2 activation loop for both the binding of Hsp90 by Slt2 and the catalytic activation of cell integrity signaling.

Targeting Oxidative Stress and Endothelial Dysfunction Using Tanshinone IIA for the Treatment of Tissue Inflammation and Fibrosis.

Salvia miltiorrhiza Burge (Danshen), a member of the Lamiaceae family, has been used in traditional Chinese medicine for many centuries as a valuable medicinal herb with antioxidative, anti-inflammatory, and antifibrotic potential. Several evidence-based reports have suggested that Salvia miltiorrhiza and its components prevent vascular diseases, including myocardial infarction, myocardial ischemia/reperfusion injury, arrhythmia, cardiac hypertrophy, and cardiac fibrosis. Tanshinone IIA (TanIIA), a lipophilic component of Salvia miltiorrhiza, has gained attention because of its possible preventive and curative activity against cardiovascular disorders. TanIIA, which possesses antioxidative, anti-inflammatory, and antifibrotic properties, could be a key component in the therapeutic potential of Salvia miltiorrhiza. Vascular diseases are often initiated by endothelial dysfunction, which is accompanied by vascular inflammation and fibrosis. In this review, we summarize how TanIIA suppresses tissue inflammation and fibrosis through signaling pathways such as PI3K/Akt/mTOR/eNOS, TGF-β1/Smad2/3, NF-κB, JNK/SAPK (stress-activated protein kinase)/MAPK, and ERK/Nrf2 pathways. In brief, this review illustrates the therapeutic value of TanIIA in the alleviation of oxidative stress, inflammation, and fibrosis, which are critical components of cardiovascular disorders.

RNA-Seq Reveals the Role of miR-29c in Regulating Inflammation and Oxidative Stress of Bovine Mammary Epithelial Cells.

Healthy mammary gland is essential for milk performance in dairy cows. MicroRNAs (miRNAs) are the key molecules to regulate the steady state of mammary gland in dairy cows. This study investigated the potential role of miR-29c in bovine mammary epithelial cells (bMECs). RNA sequencing (RNA-seq) was used to measure the transcriptome profile of bovine mammary epithelial cells line (MAC-T) transfected with miR-29c inhibitor or negative control (NC) inhibitor, and then differentially expressed genes (DEGs) were screened. The results showed that a total of 42 up-regulated and 27 down-regulated genes were found in the miR-29c inhibitor group compared with the NC inhibitor group. The functional enrichment of the above DEGs indicates that miR-29c is a potential regulator of oxidative stress and inflammatory response in bMECs through multiple genes, such as forkhead box O1 (FOXO1), tumor necrosis factor-alpha (TNF-α), and major histocompatibility complex, class II, DQ alpha 5 (BoLA-DQA5) in the various biological process and signaling pathways of stress-activated mitogen-activated protein kinase (MAPK) cascade, Epstein-Barr virus infection, inflammatory bowel disease, etc. The results imply that miR-29c plays an important role in a steady state of bMECs or cow mammary gland and may be a potential therapeutic target for mastitis in dairy cows.

Raspberry and blackberry act in a synergistic manner to improve cardiac redox proteins and reduce NF-κB and SAPK/JNK in mice fed a high-fat, high-sucrose diet

Background and aimsIncreased cardiac inflammation and oxidative stress are common features in obesity, and toll-like receptor (TLR)4 signaling is a key inflammatory pathway in this deleterious process. This study aimed to investigate whether berries could attenuate the detrimental effects of a high-fat, high-sucrose (HFHS) diet on the myocardium at the molecular level. Methods and resultsEight-week-old male C57BL/6 mice consumed a low-fat, low-sucrose (LFLS) diet alone or supplemented with 10% blackberry (BL), 10% raspberry (RB) or 10% blackberry + raspberry (BL + RB) for four weeks. Animals were then switched to a HFHS diet for 24 weeks with or without berry supplementation or maintained on a LFLS control diet without berry supplementation. Left ventricles of the heart were isolated for protein and mRNA analysis. Berry consumption, particularly BL + RB reduced NADPH-oxidase (NOX)1 and NOX2 and increased catalase (CAT) and superoxide dismutase (SOD)2, expression while BL and RB supplementation alone was less efficacious. Downstream TLR4 signaling was attenuated mostly by both RB and BL + RB supplementation, while NF-κB pathway was attenuated by BL + RB supplementation. Stress-activated protein kinase (SAPK)/Jun amino-terminal kinase (JNK) was also attenuated by BL + RB supplementation, and reduced TNF-α transcription and protein expression was observed only with BL + RB supplementation. ConclusionThe synergistic effects of BL + RB may reduce obesity-induced cardiac inflammation and oxidative stress to a greater extent than BL or RB alone.

Natural Phaeosphaeride A Derivatives Overcome Drug Resistance of Tumor Cells and Modulate Signaling Pathways.

In the present study, natural phaeosphaeride A (PPA) derivatives are synthesized. Anti-tumor studies are carried out on the PC3, K562, HCT-116, THP-1, MCF-7, A549, NCI-H929, Jurkat, and RPMI8226 tumor cell lines, and on the human embryonic kidney (HEK293) cell line. All the compounds synthesized turned out to have better efficacy than PPA towards the tumor cell lines listed. Among them, three compounds exhibited an ability to overcome the drug resistance of tumor cells associated with the overexpression of the P-glycoprotein by modulating the work of this transporter. Luminex xMAP technology was used to assess the effect of five synthesized compounds on the activation of intracellular kinase cascades in A431 cells. MILLIPLEX MAP Multi-Pathway Magnetic Bead 9-Plex was used, which allowed for the simultaneous detection of the following nine phosphorylated protein markers of the main intracellular signaling pathways: a universal transcription factor that controls the expression of immune-response genes, apoptosis and cell cycle NFκB (pS536); cAMP-dependent transcription factor (CREB (pS133); mitogen-activated kinase p38 (pT180/pY182); stress-activated protein kinase JNK (pT183/pY185); ribosomal SK; transcription factors STAT3 (pS727) and STAT5A/B (pY694/699); protein kinase B (Akt) (pS473); and kinase regulated by extracellular signals ERK1/2 (pT185/pY187). The effect of various concentrations of PPA derivatives on the cell culture was studied using xCelligence RTCA equipment. The compounds were found to modulate JNK, ERK1/2, and p38 signaling pathways. The set of activated kinase cascades suggests that oxidative stress is the main probable mechanism of the toxic action of PPA derivatives.

The HOG pathway and the regulation of osmoadaptive responses in yeast.

Cells coordinate intracellular activities in response to changes in the extracellular environment to maximize their probability of survival and proliferation. Eukaryotic cells need to adapt to constant changes in the osmolarity of their environment. In yeast, the high-osmolarity glycerol (HOG) pathway is responsible for the response to high osmolarity. Activation of the Hog1 stress-activated protein kinase (SAPK) induces a complex program required for cellular adaptation that includes temporary arrest of cell cycle progression, adjustment of transcription and translation patterns, and the regulation of metabolism, including the synthesis and retention of the compatible osmolyte glycerol. Hog1 is a member of the family of p38 SAPKs, which are present across eukaryotes. Many of the properties of the HOG pathway and downstream-regulated proteins are conserved from yeast to mammals. This review addresses the global view of this signaling pathway in yeast, as well as the contribution of Dr Hohmann's group to its understanding.

MSK-Mediated Phosphorylation of Histone H3 Ser28 Couples MAPK Signalling with Early Gene Induction and Cardiac Hypertrophy.

Heart failure is a leading cause of death that develops subsequent to deleterious hypertrophic cardiac remodelling. MAPK pathways play a key role in coordinating the induction of gene expression during hypertrophy. Induction of the immediate early gene (IEG) response including activator protein 1 (AP-1) complex factors is a necessary and early event in this process. How MAPK and IEG expression are coupled during cardiac hypertrophy is not resolved. Here, in vitro, in rodent models and in human samples, we demonstrate that MAPK-stimulated IEG induction depends on the mitogen and stress-activated protein kinase (MSK) and its phosphorylation of histone H3 at serine 28 (pH3S28). pH3S28 in IEG promoters in turn recruits Brg1, a BAF60 ATP-dependent chromatin remodelling complex component, initiating gene expression. Without MSK activity and IEG induction, the hypertrophic response is suppressed. These studies provide new mechanistic insights into the role of MAPK pathways in signalling to the epigenome and regulation of gene expression during cardiac hypertrophy.