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)

Malignant gliomas represent one of the most aggressive forms of brain cancer. Recent advances in the understanding of the deregulated molecular pathways of gliomas have brought about targeted therapies that have the ability to increase therapeutic efficacy in tumors while decreasing toxicity. Multi-targeted kinase inhibitors, novel monoclonal antibodies, and new vaccines have been developed. Standard treatments and current development of new therapies for malignant gliomas are reviewed, focusing specifically on growth factors and their receptors (e.g. epidermal growth factor receptor, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor), as well as the intracellular effector molecules that are downstream of these growth factors (e.g. Ras/Raf/mitogen-activated protein kinase, phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin, and protein kinase C). The efficacies of other novel targeted inhibitors such as deacetylase inhibitors and heat shock protein 90 inhibitors in the treatment of gliomas are also discussed, as well as new combination therapies. In order for new agents to increase treatment efficacy, new targets need to be developed, drug delivery efficiency needs to be improved, and new biomarkers need to be discovered. All of these goals can be accomplished with time through innovative experimental designs.
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PMID:Targeted therapies for malignant glioma: progress and potential. 1934 89

The role of celastrol, a triterpene extracted from the Chinese "Thunder of God Vine," in allergic inflammation was investigated. Celastrol decreased the secretion of beta-hexosaminidase, decreased the release of histamine, decreased the expression of Th2 cytokines and decreased calcium influx and cell adhesion in antigen-stimulated RBL2H3 cells. Exposure to celastrol decreased the phosphorylation of extracellular regulated kinase (ERK) and the ERK kinase activity was decreased in RBL2H3 cells. A molecular dynamics simulation showed binding of celastrol to a large pocket in ERK2, which serves as the ATP-binding site. Exposure to celastrol inhibited the interaction between immunoglobulin Fc epsilon receptor I (FcepsilonRIgamma) and ERK and inhibited interaction between FcepsilonRIgamma and protein kinase C delta (PKCdelta). Antigen stimulation induced an interaction between Rac1 and ERK as well as an interaction between Rac1 and PKCdelta. Inhibition of ERK decreased Rac1 activity and inhibition of Rac1 decreased ERK activity in antigen-stimulated RBL2H3 cells. Celastrol regulated the expression of epithelial-mesenchymal transition (EMT)-related proteins through inhibition of PKCalpha, PKCdelta, and Rac1 in antigen-stimulated RBL2H3 cells. Exposure to celatrol inhibited PKCdelta activity in antigen-stimulated RBL2H3 cells. Celastrol exerted a negative effect on FcepsilonRIbeta signaling by inhibiting the interaction between heat shock protein 90 (hsp90) and proteins, such as, FcepsilonRIbeta, Akt and PKCalpha. Celastrol exerted a negative effect on in vivo atopic dermatitis induced by 2, 4-dinitrofluorobenzene (DNFB), which requires ERK. Celastrol also showed an inhibitory effect on skin inflammation induced by phorbol myristate acetate (PMA) in Balb/c mice. In summary, celastrol binds to ERK and inhibits FcepsilonRI signaling to exert an anti-inflammatory effect.
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PMID:Celastrol binds to ERK and inhibits FcepsilonRI signaling to exert an anti-allergic effect. 1935 29

The effect of low-intensity lases light (0.2 mW/cm2, 632.8 nm, exposure time 1 min) or centimeter waves (8.15-18 GHz, 1 W/cm2, exposure time 1 h) on PhosphoSAPK/JNK production in mice lymphocytes was investigated. Normal isolated spleen lymphocytes or cells incubated previously with geldanamycin, an inhibitor of heat shock protein 90 (HSP90), were used in the experiments. A significant stimulation of PhosphoSAPK/JNK production in lymphocytes after treatment with laser light or microwaves has been shown in both cell models. It was proposed that the activation of SAPK/JNK signal pathway plays one of the central roles in cellular stress response to low-power nonionizing radiation.
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PMID:[The role of protein kinase SAPK/JNK in cell responses to low-intensity nonionizing radiation]. 1940 37

Triple-negative breast cancers (TNBCs) are defined by a lack of expression of estrogen, progesterone, and HER2 receptors. Because of the absence of identified targets and targeted therapies, and due to a heterogeneous molecular presentation, treatment guidelines for patients with TNBC include only conventional chemotherapy. Such treatment, while effective for some, leaves others with high rates of early relapse and is not curative for any patient with metastatic disease. Here, we demonstrate that these tumors are sensitive to the heat shock protein 90 (Hsp90) inhibitor PU-H71. Potent and durable anti-tumor effects in TNBC xenografts, including complete response and tumor regression, without toxicity to the host are achieved with this agent. Notably, TNBC tumors respond to retreatment with PU-H71 for several cycles extending for over 5 months without evidence of resistance or toxicity. Through a proteomics approach, we show that multiple oncoproteins involved in tumor proliferation, survival, and invasive potential are in complex with PU-H71-bound Hsp90 in TNBC. PU-H71 induces efficient and sustained downregulation and inactivation, both in vitro and in vivo, of these proteins. Among them, we identify downregulation of components of the Ras/Raf/MAPK pathway and G(2)-M phase to contribute to its anti-proliferative effect, degradation of activated Akt and Bcl-xL to induce apoptosis, and inhibition of activated NF-kappaB, Akt, ERK2, Tyk2, and PKC to reduce TNBC invasive potential. The results identify Hsp90 as a critical and multimodal target in this most difficult to treat breast cancer subtype and support the use of the Hsp90 inhibitor PU-H71 for clinical trials involving patients with TNBC.
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PMID:Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. 1941 31

The mutant JAK2V617F tyrosine kinase (TK) is present in the majority of patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs). JAK2V617F activates downstream signaling through the signal transducers and activators of transcription (STAT), RAS/mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3 (PI3)/AKT pathways, conferring proliferative and survival advantages in the MPN hematopoietic progenitor cells (HPCs). Treatment with the pan-histone deacetylase (HDAC) inhibitor panobinostat (PS) is known to inhibit the chaperone function of heat shock protein 90, as well as induce growth arrest and apoptosis of transformed HPCs. Here, we demonstrate that PS treatment depletes the autophosphorylation, expression, and downstream signaling of JAK2V617F. Treatment with PS also disrupted the chaperone association of JAK2V617F with hsp90, promoting proteasomal degradation of JAK2V617F. PS also induced apoptosis of the cultured JAK2V617F-expressing human erythroleukemia HEL92.1.7 and Ba/F3-JAK2V617F cells. Treatment with the JAK2 TK inhibitor TG101209 attenuated JAK2V617F autophosphorylation and induced apoptosis of HEL92.1.7 and Ba/F3-JAK2V617F cells. Cotreatment with PS and TG101209 further depleted JAK/STAT signaling and synergistically induced apoptosis of HEL92.1.7 and Ba/F3-JAK2V617F cells. Cotreatment with TG101209 and PS exerted greater cytotoxicity against primary CD34(+) MPN cells than normal CD34(+) HPCs. These in vitro findings suggest combination therapy with HDAC and JAK2V617F inhibitors is of potential value for the treatment of JAK2V617F-positive MPN.
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PMID:Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. 1982 2

Cerebral hypoxia is one of the main causes of cerebral injury. This study was conducted to investigate the potential protective effect of H(2)S in in vitro hypoxic models by subjecting SH-SY5Y cells to either oxygen-glucose deprivation or Na(2)S(2)O(4) (an oxygen scavenger) treatment. We found that treatment with NaHS (an H(2)S donor, 10-100 microM) 15 min prior to hypoxia increased cell viability in a concentration-dependent manner. Time-course study showed that NaHS was able to exert its protective effect even when added 8 h before or less than 4 h after hypoxia induction. Interestingly, endogenous H(2)S level was markedly reduced by hypoxia induction. Over-expression of cystathionine-beta-synthase prevented hypoxia induced cell apoptosis. Blockade of ATP-sensitive K(+) (K(ATP)) channels with glibenclamide and HMR-1098, protein kinase C (PKC) with its three specific inhibitors (chelerythrine, bisindolylmaleide I and calphostin C), extracellular signal-regulated kinase 1/2 (ERK1/2) with PD98059 and heat shock protein 90 (Hsp90) with geldanamycin and radicicol significantly attenuated the protective effects of NaHS. Western blots showed that NaHS significantly stimulated ERK1/2 activation and Hsp90 expression. In conclusion, H(2)S exerts a protective effect against cerebral hypoxia induced neuronal cell death via K(ATP)/PKC/ERK1/2/Hsp90 pathway. Our findings emphasize the important neuroprotective role of H(2)S in the brain during cerebral hypoxia.
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PMID:Hydrogen sulfide protects neurons against hypoxic injury via stimulation of ATP-sensitive potassium channel/protein kinase C/extracellular signal-regulated kinase/heat shock protein 90 pathway. 2014 43

The past decade has witnessed a dramatic improvement in the therapeutic options in multiple myeloma (MM). Several novel biologically targeted agents are in clinical use and have resulted in improved outcomes. However, the disease remains incurable, underscoring the need for continued efforts towards understanding MM biology, better risk stratification and exploitation of novel therapeutic approaches. Novel agents that target tumor and stromal compartments can be categorized as those that target protein dynamics (e.g., heat shock protein 90 and the ubiquitin-proteasome system), intracellular signaling kinases (e.g., JAK/STAT, PI3k/Akt/mTOR and MAPK pathways), cell cycle molecular machinery (e.g., cyclin-dependent kinase inhibitor and Aurora kinase inhibitors), membrane-bound receptors (e.g., IGF-1, VEGF and CD40), epigenetic modulators (e.g., DNA methyltransferase and histone deacetylase), tumor vasculature and microenvironment (e.g., angiogenesis and integrins) and agents modulating anti-MM immune responses. This article focuses on a series of new therapeutic targets that have shown promising preclinical results and early evidence of anti-MM activity in clinical studies, either alone or in combination with other conventional or novel anti-MM treatments.
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PMID:Novel therapeutic targets for multiple myeloma. 2022 97

In 2006 there were 60,000 new cases of cutaneous melanoma in the European Union and 13,000 deaths (www.europeancancerleagues. org). Currently available systemic treatment options for metastatic melanoma, including both cytotoxic and immunologic therapies, produce low rates of response and have modest survival impact. Therefore, there is an urgent need for effective novel therapies. Molecularly targeted treatments have demonstrated efficacy in certain cancers e.g. in HER2- positive breast cancer and in chronic myeloid leukaemia. Several pathways are currently being investigated as potential molecular targets in melanoma. The best studied is BRAF which is frequently mutated in melanoma. A multi tyrosine kinase inhibitor, sorafenib, which targets BRAF, has shown promising activity in preclinical studies and is currently being tested in combination with chemotherapy in patients with metastatic disease. In addition to BRAF, therapies which target other components of the Raf/Ras/MAPK pathway are being investigated. Other novel targets currently being investigated include the PI3/AKT pathway, tyrosine kinases, angiogenesis, poly (ADP ribose) polymerases, survivin and heat shock protein 90. Progress on preclinical and clinical evaluation of these novel targets in melanoma will be reviewed.
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PMID:Prospects for non-immunological molecular therapeutics in melanoma. 2041 21

The present studies determine in greater detail the molecular mechanisms upstream of the CD95 death receptor by which geldanamycin heat shock protein 90 inhibitors and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 (MEK1/2) inhibitors interact to kill carcinoma cells. MEK1/2 inhibition enhanced 17-allylamino-17-demethoxygeldanamycin (17AAG) toxicity that was suppressed in cells deleted for mutant active RAS that were nontumorigenic but was magnified in isogenic tumorigenic cells expressing Harvey RAS V12 or Kirsten RAS D13. MEK1/2 inhibitor and 17AAG treatment increased intracellular Ca(2+) levels and reduced GRP78/BiP expression in a Ca(2+)-dependent manner. GRP78/BiP overexpression, however, also suppressed drug-induced intracellular Ca(2+) levels. MEK1/2 inhibitor and 17AAG treatment increased reactive oxygen species (ROS) levels that were blocked by quenching Ca(2+) or overexpression of GRP78/BiP. MEK1/2 inhibitor and 17AAG treatment activated CD95 and inhibition of ceramide synthesis; ROS or Ca(2+) quenching blocked CD95 activation. In SW620 cells that are patient matched to SW480 cells, MEK1/2 inhibitor and 17AAG toxicity was significantly reduced, which correlated with a lack of CD95 activation and lower expression of ceramide synthase 6 (LASS6). Overexpression of LASS6 in SW620 cells enhanced drug-induced CD95 activation and enhanced tumor cell killing. Inhibition of ceramide signaling abolished drug-induced ROS generation but not drug-induced cytosolic Ca(2+) levels. Thus, treatment of tumor cells with MEK1/2 inhibitor and 17AAG induces cytosolic Ca(2+) and loss of GRP78/BiP function, leading to de novo ceramide synthesis pathway activation that plays a key role in ROS generation and CD95 activation.
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PMID:17-allylamino-17-demethoxygeldanamycin and MEK1/2 inhibitors kill GI tumor cells via Ca2+-dependent suppression of GRP78/BiP and induction of ceramide and reactive oxygen species. 2044 8

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates biological and toxicological effects by binding to its agonists such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Previously we demonstrated that flavonoids suppressed the TCDD-induced DNA-binding activity of the AhR in a structure-dependent manner. In this study, we investigated the mechanisms by which flavonoids suppressed the AhR-mediated signal transduction in mouse hepatoma Hepa-1c1c7 cells. Flavones and flavonols suppressed the TCDD-induced nuclear translocation of the AhR and dissociation of its partner proteins, heat shock protein 90 and X-associated protein 2, whereas flavanones and catechins did not. Flavonoids of all these four subclasses suppressed the phosphorylation of both AhR and Arnt and the formation of a heterodimer consisting of these proteins. Since certain flavonoids are known to inhibit mitogen-activated protein kinases (MAPKs), we confirmed the contribution of MAPK/ERK kinase (MEK) to the AhR-mediated signal transduction by using U0126, an inhibitor of MEK1/2. U0126 suppressed TCDD-induced phosphorylation of the AhR and Arnt followed by the DNA-binding activity of the AhR. Flavanones and catechins suppressed the TCDD-induced phosphorylation of ERK1/2. The inhibition of MEK/ERK phosphorylation is one of the mechanisms by which flavanones and catechins suppress the AhR-mediated signal transduction in Hepa-1c1c7 cells.
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PMID:Suppression mechanisms of flavonoids on aryl hydrocarbon receptor-mediated signal transduction. 2045 Aug 80


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