Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Direct and indirect roles of cyclin-dependent kinase 5 as an upstream regulator in the c-Jun NH2-terminal kinase cascade: relevance to neurotoxic insults in Alzheimer's disease.

ABSTRACT: Significant increase in JNK, c-Jun, and Cdk5 activities are reported in Alzheimer's disease (AD). Inhibition of c-Jun prevents neuronal cell death in in vivo AD models, highlighting it as a major JNK effector. Both JNK and Cdk5 promote neurodegeneration upon deregulation; however, Cdk5 has not been mechanistically linked to JNK or c-Jun. This study presents the first mechanism showing Cdk5 as a major regulator of the JNK cascade. Deregulated Cdk5 induces biphasic activation of JNK pathway. The first phase revealed c-Jun as a direct substrate of Cdk5, whose activation is independent of reactive oxygen species (ROS) and JNK. In the second phase, Cdk5 activates c-Jun via ROS-mediated activation of JNK. Rapid c-Jun activation is supported by in vivo data showing c-Jun phosphorylation in cerebral cortex upon p25 induction in transgenic mice. Cdk5-mediated biphasic activation of c-Jun highlights c-Jun, rather than JNK, as an important therapeutic target, which was confirmed in neuronal cells. Finally, Cdk5 inhibition endows superior protection against neurotoxicity, suggesting that Cdk5 is a preferable therapeutic target for AD relative to JNK and c-Jun.

SUBMITTER: Sun KH

PROVIDER: S-EPMC2770948 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase.

Project description:The c-Jun NH2-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases is activated by phosphorylation on Thr and Tyr. Here we report the molecular cloning of a new member of the mammalian MAP kinase kinase group (MKK7) that functions as an activator of JNK. In vitro protein kinase assays demonstrate that MKK7 phosphorylates and activates JNK, but not the p38 or extracellular signal-regulated kinase groups of MAP kinase. Expression of MKK7 in cultured cells causes activation of the JNK signal transduction pathway. MKK7 is therefore established to be a novel component of the JNK signal transduction pathway.

| S-EPMC23822 | biostudies-literature

c-Jun-NH2-kinase-1 inhibition leads to antitumor activity in ovarian cancer.

Project description:To show the functional, clinical, and biological significance of c-Jun-NH(2)-kinase (JNK)-1 in ovarian carcinoma.Analysis of the impact of JNK on 116 epithelial ovarian cancers was conducted. The role of JNK in vitro and in experimental models of ovarian cancer was assessed. We studied the role of N-5-[4-(4-methyl piperazine methyl)-benzoylamido]-2-methylphenyl-4-[3-(4-methyl)-pyridyl]-2-pyrimidine amine (WBZ_4), a novel JNK inhibitor redesigned from imatinib based on targeting wrapping defects, in cell lines and in experimental models of ovarian cancer.We found a significant association of pJNK with progression-free survival in the 116 epithelial ovarian cancers obtained at primary debulking therapy. WBZ_4 led to cell growth inhibition and increased apoptosis in a dose-dependent fashion in four ovarian cancer cell lines. In vivo, whereas imatinib had no effect on tumor growth, WBZ_4 inhibited tumor growth in orthotopic murine models of ovarian cancer. The antitumor effect was further increased in combination with docetaxel. Silencing of JNK-1 with systemically administered siRNA led to significantly reduced tumor weights compared with nonsilencing siRNA controls, indicating that indeed the antitumor effects observed were due to JNK-1 inhibition.These studies identify JNK-1 as an attractive therapeutic target in ovarian carcinoma and that the redesigned WBZ_4 compound should be considered for further clinical development.

| S-EPMC3716580 | biostudies-literature

Tumor necrosis factor receptor 1/c-Jun-NH2-kinase signaling promotes human neoplasia.

Project description:The tumor necrosis factor alpha receptor (TNFR1) activates downstream effectors that include the mitogen-activated protein kinase kinase 7 (MKK7)/c-Jun-NH(2)-kinase (JNK)/activator protein 1 (AP1) cascade. Here, we report that JNK is activated in a majority of spontaneous human squamous cell carcinomas (SCC). JNK pathway induction bypassed cell cycle restraints induced by oncogenic Ras and cooperated with Ras to convert normal human epidermis into tumors indistinguishable from SCC, confirming its oncogenic potency in human tissue. Inhibiting MKK7, JNK, and AP1 as well as TNFR1 itself using genetic, pharmacologic, or antibody-mediated approaches abolished invasive human epidermal neoplasia in a tumor cell autonomous fashion. The TNFR1/MKK7/JNK/AP1 cascade thus promotes human neoplasia and represents a potential therapeutic target for human epithelial cancers.

| S-EPMC2239246 | biostudies-literature

The MKK7 gene encodes a group of c-Jun NH2-terminal kinase kinases.

Project description:The c-Jun NH2-terminal protein kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) group and is an essential component of a signaling cascade that is activated by exposure of cells to environmental stress. JNK activation is regulated by phosphorylation on both Thr and Tyr residues by a dual-specificity MAPK kinase (MAPKK). Two MAPKKs, MKK4 and MKK7, have been identified as JNK activators. Genetic studies demonstrate that MKK4 and MKK7 serve nonredundant functions as activators of JNK in vivo. We report here the molecular cloning of the gene that encodes MKK7 and demonstrate that six isoforms are created by alternative splicing to generate a group of protein kinases with three different NH2 termini (alpha, beta, and gamma isoforms) and two different COOH termini (1 and 2 isoforms). The MKK7alpha isoforms lack an NH2-terminal extension that is present in the other MKK7 isoforms. This NH2-terminal extension binds directly to the MKK7 substrate JNK. Comparison of the activities of the MKK7 isoforms demonstrates that the MKK7alpha isoforms exhibit lower activity, but a higher level of inducible fold activation, than the corresponding MKK7beta and MKK7gamma isoforms. Immunofluorescence analysis demonstrates that these MKK7 isoforms are detected in both cytoplasmic and nuclear compartments of cultured cells. The presence of MKK7 in the nucleus was not, however, required for JNK activation in vivo. These data establish that the MKK4 and MKK7 genes encode a group of protein kinases with different biochemical properties that mediate activation of JNK in response to extracellular stimuli.

| S-EPMC116085 | biostudies-literature

c-Jun NH2-terminal kinase 2 inhibits gamma interferon production during Anaplasma phagocytophilum infection.

Project description:Gamma interferon (IFN-gamma) plays a critical role in the early eradication of Anaplasma phagocytophilum. However, the mechanisms that regulate IFN-gamma production upon infection remain poorly understood. Here we show that c-Jun NH2-terminal kinase 2 (JNK2) inhibits IFN-gamma production during A. phagocytophilum infection. jnk2-null mice were more refractory to infection with A. phagocytophilum and produced increased levels of IFN-gamma after challenge with the pathogen. The resistance of jnk2-null mice to A. phagocytophilum infection was due to elevated levels of IFN-gamma secreted by conventional and natural killer (NK) T cells. The administration of alpha-galactosylceramide, a strong NK T-cell agonist, increased IFN-gamma release and protected mice from A. phagocytophilum, further demonstrating the inhibitory effect of JNK2 on IFN-gamma production. Collectively, these findings provide strong evidence that JNK2 is an important regulatory protein for IFN-gamma secretion upon challenge with A. phagocytophilum.

| S-EPMC2223674 | biostudies-literature

SIRT2 regulates oxidative stress-induced cell death through deacetylation of c-Jun NH2-terminal kinase.

Project description:c-Jun NH2-terminal kinases (JNKs) are responsive to stress stimuli and their activation regulate key cellular functions, including cell survival, growth, differentiation and aging. Previous studies demonstrate that activation of JNK requires dual phosphorylation by the mitogen-activated protein kinase kinases. However, other post-translational mechanisms involved in regulating the activity of JNK have been poorly understood. In this work, we studied the functional significance of reversible lysine acetylation in regulating the kinase activity of JNK. We found that the acetyl transferase p300 binds to, acetylates and inhibits kinase activity of JNK. Using tandem mass spectrometry, molecular modelling and molecular dynamics simulations, we found that acetylation of JNK at Lys153 would hinder the stable interactions of the negatively charged phosphates and prevent the adenosine binding to JNK. Our screening for the deacetylases found SIRT2 as a deacetylase for JNK. Mechanistically, SIRT2-dependent deacetylation enhances ATP binding and enzymatic activity of JNK towards c-Jun. Furthermore, SIRT2-mediated deacetylation favours the phosphorylation of JNK by MKK4, an upstream kinase. Our results indicate that deacetylation of JNK by SIRT2 promotes oxidative stress-induced cell death. Conversely, SIRT2 inhibition attenuates H2O2-mediated cell death in HeLa cells. SIRT2-deficient (SIRT2-KO) mice exhibit increased acetylation of JNK, which is associated with markedly reduced catalytic activity of JNK in the liver. Interestingly, SIRT2-KO mice were resistant to acetaminophen-induced liver toxicity. SIRT2-KO mice show lower cell death, minimal degenerative changes, improved liver function and survival following acetaminophen treatment. Overall, our work identifies SIRT2-mediated deacetylation of JNK as a critical regulator of cell survival during oxidative stress.

| S-EPMC6143545 | biostudies-literature

The c-Jun NH2-terminal kinase 2 plays a dominant role in human epidermal neoplasia.

Project description:The c-Jun NH(2)-terminal kinase (JNK) signaling cascade has been implicated in a wide range of diseases, including cancer. It is unclear how different JNK proteins contribute to human cancer. Here, we report that JNK2 is activated in more than 70% of human squamous cell carcinoma (SCC) samples and that inhibition of JNK2 pharmacologically or genetically impairs tumorigenesis of human SCC cells. Most importantly, JNK2, but not JNK1, is sufficient to couple with oncogenic Ras to transform primary human epidermal cells into malignancy with features of SCC. JNK2 prevents Ras-induced cell senescence and growth arrest by reducing the expression levels of the cell cycle inhibitor p16 and the activation of NF-kappaB. On the other hand, JNK, along with phosphoinositide 3-kinase, is essential for Ras-induced glycolysis, an energy-producing process known to benefit cancer growth. These data indicate that JNK2 collaborates with other oncogenes, such as Ras, at multiple molecular levels to promote tumorigenesis and hence represents a promising therapeutic target for cancer.

| S-EPMC2855785 | biostudies-literature

Molecular cloning and characterization of human JNKK2, a novel Jun NH2-terminal kinase-specific kinase.

Project description:At least three mitogen-activated protein kinase (MAPK) cascades were identified in mammals, each consisting of a well-defined three-kinase module composed of a MAPK, a MAPK kinase (MAPKK), and a MAPKK kinase (MAPKKK). These cascades play key roles in relaying various physiological, environmental, or pathological signals from the environment to the transcriptional machinery in the nucleus. One of these MAPKs, c-Jun N-terminal kinase (JNK), stimulates the transcriptional activity of c-Jun in response to growth factors, proinflammatory cytokines, and certain environmental stresses, such as short wavelength UV light or osmotic shock. The JNKs are directly activated by the MAPKK JNKK1/SEK1/MKK4. However, inactivation of the gene encoding this MAPKK by homologous recombination suggested the existence of at least one more JNK-activating kinase. Recently, the JNK cascade was found to be structurally and functionally conserved in Drosophila, where DJNK is activated by the MAPKK DJNKK (hep). By a database search, we identified an expressed sequence tag (EST) encoding a portion of human MAPKK that is highly related to DJNKK (hep). We used this EST to isolate a full-length cDNA clone encoding a human JNKK2. We show that JNKK2 is a highly specific JNK kinase. Unlike JNKK1, it does not activate the related MAPK, p38. Although the regulation of JNKK1 activities and that of JNKK2 activities could be very similar, the two kinases may play somewhat different regulatory roles in a cell-type-dependent manner.

| S-EPMC232596 | biostudies-other

Doxorubicin requires the sequential activation of caspase-2, protein kinase Cdelta, and c-Jun NH2-terminal kinase to induce apoptosis.

Project description:Here, we identified caspase-2, protein kinase C (PKC)delta, and c-Jun NH2-terminal kinase (JNK) as key components of the doxorubicin-induced apoptotic cascade. Using cells stably transfected with an antisense construct for caspase-2 (AS2) as well as a chemical caspase-2 inhibitor, we demonstrate that caspase-2 is required in doxorubicin-induced apoptosis. We also identified PKCdelta as a novel caspase-2 substrate. PKCdelta was cleaved/activated in a caspase-2-dependent manner after doxorubicin treatment both in cells and in vitro. PKCdelta is furthermore required for efficient doxorubicin-induced apoptosis because its chemical inhibition as well as adenoviral expression of a kinase dead (KD) mutant of PKCdelta severely attenuated doxorubicin-induced apoptosis. Furthermore, PKCdelta and JNK inhibition show that PKCdelta lies upstream of JNK in doxorubicin-induced death. Jnk-deficient mouse embryo fibroblasts (MEFs) were highly resistant to doxorubicin compared with wild type (WT), as were WT Jurkat cells treated with SP600125, further supporting the importance of JNK in doxorubicin-induced apoptosis. Chemical inhibitors for PKCdelta and JNK do not synergize and do not function in doxorubicin-treated AS2 cells. Caspase-2, PKCdelta, and JNK were furthermore implicated in doxorubicin-induced apoptosis of primary acute lymphoblastic leukemia blasts. The data thus support a sequential model involving caspase-2, PKCdelta, and JNK signaling in response to doxorubicin, leading to the activation of Bak and execution of apoptosis.

| S-EPMC1182319 | biostudies-literature

Testosterone prevents the heat shock-induced overactivation of glycogen synthase kinase-3 beta but not of cyclin-dependent kinase 5 and c-Jun NH2-terminal kinase and concomitantly abolishes hyperphosphorylation of tau: implications for Alzheimer's disease.

Project description:We have shown previously that glycogen synthase kinase-3 beta (GSK-3 beta), cyclin-dependent kinase 5, and c-Jun NH(2)-terminal kinase become overactivated and hyperphosphorylate tau in heat-shocked female rats. This hyperphosphorylation of tau is estrogen-independent, prevented by androgens, and similar to Alzheimer's disease. In this study, ovariectomized (OVX) Sprague-Dawley rats (n = 75) received daily injections of 10 microg of 17 beta-estradiol benzoate (EB), or 250 microg of testosterone propionate (TP), or both EB and TP, or sesame oil (SO) vehicle for 4-6 weeks. In kinase assays of forebrain homogenates, overactivation of GSK-3 beta at 0-6 h after heat shock toward human recombinant tau, bovine tau, and phosphoglycogen synthase peptide 2 was prevented in OVX + TP and OVX + (EB + TP) but not in sham-OVX + SO, OVX + SO, and OVX + EB. Abs against inactive (pSer(9)) and activity-enhanced (pTyr(216)) GSK-3 beta showed marked increase of pSer(9)- and decrease of pTyr(216)-GSK-3 beta in both OVX + TP and OVX + (EB + TP) but not in sham-OVX + SO, OVX + SO, and OVX + EB. EB enhanced the overactivation of cyclin-dependent kinase 5. The activity of c-Jun NH(2)-terminal kinase was gonadal hormone-independent. The serum concentrations of testosterone and 17 beta-estradiol were 2.53 ng/ml and 201 pg/ml in OVX + TP and OVX + EB, respectively. These findings demonstrate that testosterone prevents the hyperphosphorylation of tau by inhibiting the heat shock-induced overactivation of GSK-3 beta and suggest that androgens given to aging men or, in combination with estrogens, to postmenopausal women could prevent or delay Alzheimer's disease.

| S-EPMC122157 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data