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Kinase Signaling (kinase + signaling)
Terms modified by Kinase Signaling Selected AbstractsGDNF hyperalgesia is mediated by PLC,, MAPK/ERK, PI3K, CDK5 and Src family kinase signaling and dependent on the IB4-binding protein versicanEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2008Oliver Bogen Abstract The function of the isolectin B4 (IB4+)-binding and GDNF-dependent Ret (Ret+)-expressing non-peptidergic subpopulation of nociceptors remain poorly understood. We demonstrate that acute administration of GDNF sensitizes nociceptors and produces mechanical hyperalgesia in the rat. Intrathecal IB4,saporin, a selective toxin for IB4+/Ret+ -nociceptors, attenuates GDNF but not NGF hyperalgesia. Conversely, intrathecal antisense to Trk A attenuated NGF but not GDNF hyperalgesia. Intrathecal administration of antisense oligodeoxynucleotides targeting mRNA for versican, the molecule that renders the Ret-expressing nociceptors IB4-positive (+), also attenuated GDNF but not NGF hyperalgesia, as did ADAMTS-4, a matrix metalloprotease known to degrade versican. Finally, inhibitors for all five signaling pathways known to be activated by GDNF at GFR,1/Ret: PLC,, CDK5, PI3K, MAPK/ERK and Src family kinases, attenuated GDNF hyperalgesia. Our results demonstrate a role of the non-peptidergic nociceptors in pain produced by the neurotrophin GDNF and suggest that the IB4-binding protein versican functions in the expression of this phenotype. [source] Activation of dorsal horn microglia contributes to diabetes-induced tactile allodynia via extracellular signal-regulated protein kinase signalingGLIA, Issue 4 2008Makoto Tsuda Abstract Painful neuropathy is one of the most common complications of diabetes, one hallmark of which is tactile allodynia (pain hypersensitivity to innocuous stimulation). The underlying mechanisms of tactile allodynia are, however, poorly understood. Emerging evidence indicates that, following nerve injury, activated microglia in the spinal cord play a crucial role in tactile allodynia. However, it remains unknown whether spinal microglia are activated under diabetic conditions and whether they contribute to diabetes-induced tactile allodynia. In the present study, using streptozotocin (STZ)-induced diabetic rats that displayed tactile allodynia, we found several morphological changes of activated microglia in the dorsal horn. These included increases in Iba1 and OX-42 labeling (markers of microglia), hypertrophic morphology, the thickness and the retraction of processes, and in the number of activated microglia cells. Furthermore, in the dorsal horn of STZ diabetic rats, extracellular signal-regulated protein kinase (ERK) and an upstream kinase, Src-family kinase (SFK), both of which are implicated in microglial functions, were activated exclusively in microglia. Moreover, inhibition of ERK phosphorylation in the dorsal horn by intrathecal administration of U0126, an inhibitor of ERK activation, produced a striking alleviation of existing, long-term tactile allodynia of diabetic rats. We also found that a single administration of U0126 reduced the expression of allodynia. Together, these results suggest that activated dorsal horn microglia may be a crucial component of diabetes-induced tactile allodynia, mediated, in part, by the ERK signaling pathway. Thus, inhibiting microglia activation in the dorsal horn may represent a therapeutic strategy for treating diabetic tactile allodynia. © 2008 Wiley-Liss, Inc. [source] Oncogene expression profiles in K6/ODC mouse skin and papillomas following a chronic exposure to monomethylarsonous acid,JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 6 2009Don A. Delker Abstract We have previously observed that a chronic drinking water exposure to monomethylarsonous acid [MMA(III)], a cellular metabolite of inorganic arsenic, increases tumor frequency in the skin of keratin VI/ornithine decarboxylase (K6/ODC) transgenic mice. To characterize gene expression profiles predictive of MMA(III) exposure and mode of action of carcinogenesis, skin and papilloma RNA was isolated from K6/ODC mice administered 0, 10, 50, and 100 ppm MMA(III) in their drinking water for 26 weeks. Following RNA processing, the resulting cRNA samples were hybridized to Affymetrix Mouse Genome 430A 2.0 GeneChips®. Micoarray data were normalized using MAS 5.0 software, and statistically significant genes were determined using a regularized t -test. Significant changes in bZIP transcription factors, MAP kinase signaling, chromatin remodeling, and lipid metabolism gene transcripts were observed following MMA(III) exposure as determined using the Database for Annotation, Visualization and Integrated Discovery 2.1 (DAVID) (Dennis et al., Genome Biol 2003;4(5):P3). MMA(III) also caused dose-dependent changes in multiple Rho guanine nucleotide triphosphatase (GTPase) and cell cycle related genes as determined by linear regression analyses. Observed increases in transcript abundance of Fosl1, Myc, and Rac1 oncogenes in mouse skin support previous reports on the inducibility of these oncogenes in response to arsenic and support the relevance of these genomic changes in skin tumor induction in the K6/ODC mouse model. © 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:406,418, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20304 [source] Diminished contraction-induced intracellular signaling towards mitochondrial biogenesis in aged skeletal muscleAGING CELL, Issue 4 2009Vladimir Ljubicic Summary The intent of this study was to determine whether aging affects signaling pathways involved in mitochondrial biogenesis in response to a single bout of contractile activity. Acute stimulation (1 Hz, 5 min) of the tibialis anterior (TA) resulted in a greater rate of fatigue in old (36 month), compared to young (6 month) F344XBN rats, which was associated with reduced ATP synthesis and a lower mitochondrial volume. To investigate fiber type-specific signaling, the TA was sectioned into red (RTA) and white (WTA) portions, possessing two- to 2.5-fold differences in mitochondrial content. The expression and contraction-mediated phosphorylation of p38, MKK3/6, CaMKII and AMPK, were assessed. Kinase protein expression tended to be higher in fiber sections with lower mitochondrial content, such as the WTA, relative to the RTA muscle, and this was exaggerated in tissues from senescent, compared to young animals. At rest, kinase activation was generally similar between young and old animals, despite the age-related variations in mitochondrial volume. In response to contractile activity, age did not influence the signaling of these kinases in the high-oxidative RTA muscle. However, in the low-oxidative WTA muscle, contraction-induced kinase activation was attenuated in old animals, despite the greater metabolic stress imposed by contractile activity in this muscle. Thus, the reduction of contraction-evoked kinase phosphorylation in muscle from old animals is fiber type-specific, and depends on factors which are, in part, independent of the metabolic milieu within the contracting fibers. These findings imply that the downstream consequences of kinase signaling are reduced in aging muscle. [source] The DAF-2 insulin-like signaling pathway independently regulates aging and immunity in C. elegansAGING CELL, Issue 6 2008Eric A. Evans Summary The Caenorhabditis elegans DAF-2 insulin-like signaling pathway, which regulates lifespan and stress resistance, has also been implicated in resistance to bacterial pathogens. Loss-of-function daf-2 and age-1 mutants have increased lifespans and are resistant to a variety of bacterial pathogens. This raises the possibility that the increased longevity and the pathogen resistance of insulin-like signaling pathway mutants are reflections of the same underlying mechanism. Here we report that regulation of lifespan and resistance to the bacterial pathogen Pseudomonas aeruginosa is mediated by both shared and genetically distinguishable mechanisms. We find that loss of germline proliferation enhances pathogen resistance and this effect requires daf-16, similar to the regulation of lifespan. In contrast, the regulation of pathogen resistance and lifespan is decoupled within the DAF-2 pathway. Long-lived mutants of genes downstream of daf-2, such as pdk-1 and sgk-1, show wildtype resistance to pathogens. However, mutants of akt-1 and akt-2, which we find to individually have modest effects on lifespan, show enhanced resistance to pathogens. We also demonstrate that pathogen resistance of daf-2, akt-1, and akt-2 mutants is associated with restricted bacterial colonization, and that daf-2 mutants are better able to clear an infection after challenge with P. aeruginosa. Moreover, we find that pathogen resistance among insulin-like signaling mutants is associated with increased expression of immunity genes during infection. Other processes that affect organismal longevity, including Jun kinase signaling and caloric restriction, do not affect resistance to bacterial pathogens, further establishing that aging and innate immunity are regulated by genetically distinct mechanisms. [source] BDNF activated TrkB/IRR receptor chimera promotes survival of sympathetic neurons through Ras and PI-3 kinase signalingJOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2002Karen S. Kelly-Spratt Insulin receptor-related receptor (IRR) expression is tightly coupled to the nerve growth factor (NGF) receptor, TrkA, throughout development. Expression of both receptors is primarily localized to neural crest derived sensory and sympathetic neurons. In contrast to TrkA, however, the physiological ligand for IRR is unknown. To analyze the intracellular signaling and potential function of the orphan IRR in neurons, an adenovirus expressing a TrkB/IRR chimeric receptor was used to infect cultured mouse superior cervical ganglion neurons that normally require NGF for survival. Brain derived neurotrophic factor (BDNF)-activated TrkB/IRR induced neuronal survival. We utilized numerous receptor mutants in order to identify the intracellular domains of IRR necessary for signaling and neuron survival. Finally, we employed adenovirus encoding dominant negative forms of the extracellular signal-regulated kinase (ERK) signaling cascade to demonstrate that IRR, like TrkA, requires ras activation to promote neuron survival. Therefore, by use of the chimeric TrkB/IRR receptor, we have demonstrated the ability of IRR to elicit activation of signaling cascades resulting in a biological response in superior cervical ganglion (SCG) neurons. © 2002 Wiley-Liss, Inc. [source] Ethanol Exposure Impairs LPS-Induced Pulmonary LIX Expression: Alveolar Epithelial Cell Dysfunction as a Consequence of Acute IntoxicationALCOHOLISM, Issue 2 2009James E. Walker Jr Background:, Alcohol intoxication impairs innate immune responses to bacterial pneumonia, including neutrophil influx. Lipopolysaccharide (LPS)-induced chemokine (LIX or CXCL5) is a recently described chemokine produced by type-II alveolar epithelial (AE2) cells which facilitates neutrophil recruitment. The effect of acute alcohol intoxication on AE2 cell expression of LIX is unknown. Methods:, C57BL/6 mice were given an intraperitoneal (i.p.) injection of ethanol (4 g/kg) or saline 30 minutes prior to intratracheal (i.t.) injection with 10 ,g Escherichia coli LPS. In vitro stimulation of primary AE2 cells or murine AE2 cell line MLE-12 was performed with LPS and tumor necrosis factor-alpha (TNF-,). Results:, LIX protein is readily detectable in the lung but not in plasma following LPS administration, demonstrating "compartmentalization" of this chemokine during pulmonary challenge. In contrast to the CXC chemokines keratinocyte-derived chemokine and macrophage inflammatory protein-2, which are abundantly expressed in both lung tissue and alveolar macrophages, LIX expression is largely confined to the lung parenchyma. Compared to controls, intoxicated animals show a decrease in LIX and neutrophil number in bronchoalveolar lavage fluid following LPS challenge. Ethanol inhibits LIX at the transcriptional level. In vitro studies show that LPS and TNF-, are synergistic in inducing LIX by either primary AE2 or MLE-12 cells. Acute ethanol exposure potently and dose-dependently inhibits LIX expression by AE2 cells. Activation of nuclear factor-,B is critical to LIX expression in MLE-12 cells, and acute ethanol treatment interferes with early activation of this pathway as evidenced by impairing phosphorylation of p65 (RelA). Inhibition of p38 mitogen-activated protein kinase signaling, but not ERK1/2 activity, in MLE-12 cells by acute alcohol is likely an important cause of decreased LIX expression during challenge. Conclusions:, These data demonstrate direct suppression of AE2 cell innate immune function by ethanol and add to our understanding of the mechanisms by which acute intoxication impairs the lung's response to microbial challenge. [source] S -Allyl- L -Cysteine Sulfoxide Inhibits Tumor Necrosis Factor-Alpha Induced Monocyte Adhesion and Intercellular Cell Adhesion Molecule-1 Expression in Human Umbilical Vein Endothelial CellsTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 3 2010Chai Hui Abstract Garlic and its water-soluble allyl sulfur-containing compound, S -Allyl- L -cysteine Sulfoxide (ACSO), have shown antioxidant and anti-inflammatory activities, inhibiting the development of atherosclerosis. However, little is known about the mechanism(s) underlying the therapeutic effect of ACSO in inhibiting the formation of atherosclerostic lesion. This study aimed to investigate whether ACSO could modulate tumor necrosis factor-alpha (TNF-,)-induced expression of intercellular cell adhesion molecule-1, monocyte adhesion and TNF-,-mediated signaling in human umbilical vein endothelial cells. While TNF-, promoted the intercellular cell adhesion molecule-1 mRNA transcription in a dose- and time-dependent manner, ACSO treatment significantly reduced the levels of TNF-,-induced intercellular cell adhesion molecule-1 mRNA transcripts (P < 0.01). Furthermore, ACSO dramatically inhibited TNF-, triggered adhesion of THP-1 monocytes to endothelial cells and porcine coronary artery rings. Moreover, ACSO mitigated TNF-, induced depolarization of mitochondrial membrane potential and overproduction of superoxide anion, associated with the inhibition of NOX4, a subunit of nicotinamide adenine dinucleotide phosphate-oxidase, mRNA transcription. In addition, ACSO also inhibited TNF-,-induced phosphorylation of JNK, ERK1/2 and I,B, but not p38. Apparently, ACSO inhibited proinflammatory cytokine-induced adhesion of monocytes to endothelial cells by inhibiting the mitogen-activated protein kinase signaling and related intercellular cell adhesion molecule-1 expression, maintaining mitochondrial membrane potential, and suppressing the overproduction of superoxide anion in endothelial cells. Therefore, our findings may provide new insights into ACSO on controlling TNF-,-mediated inflammation and vascular disease. Anat Rec, 2010. © 2010 Wiley-Liss, Inc. [source] Differential cytotoxicity of novel somatostatin and dopamine chimeric compounds on bronchopulmonary and small intestinal neuroendocrine tumor cell linesCANCER, Issue 4 2008Mark Kidd PhD Abstract BACKGROUND. Survival rates for gastrointestinal (GI) and bronchopulmonary (BP) neuroendocrine tumors (NETs) have not significantly altered (overall 67%, 5-year survival) in 30 years (1973-2004), whereas the incidence has increased (, 1000%) in the same time frame. No effective or specific antineoplastic agent is available for treatment, although somatostatin analogs inhibit tumor secretion. Given the coexistence of somatostatin and dopamine regulatory receptors on NET cells, the antiproliferative efficacy as well as the signaling and transcriptional targets of their ligands were evaluated. METHODS. The cytotoxic effects of 12 somatostatin/dopamine compounds were evaluated in 3 NET cell lines, and real-time polymerase chain reaction and enzyme-linked immunoadsorbent assay studies were performed to delineate antiproliferative signaling pathways. RESULTS. The atypical BP-NET, NCI-H720, was most sensitive to the sst5 analog BIM23206 (half-maximal concentration, 2.4 pM) and demonstrated similar sensitivity to lanreotide and the sst2 analog BIM23120. The typical BP-NET, NCI-H727, was most sensitive to BIM23120 (0.7 nM) and to the pan-somatostatin receptor analog (BIM23A779). The GI-NET, KRJ-I, was most sensitive to sst2,5 analogs lanreotide (1 nM) and BIM23244 (7.4 nM). Lanreotide activated extracellular signal regulated kinase-1/2 phosphorylation and p21WAF1/CIP1 transcription, but inhibited Ki-67 transcription. NCI-H720 was most sensitive to the sst2,5 - and D2 -selective compound BIM23A761 (4.2 nM), as was NCI-H727 (5.5 nM). KRJ-I did not respond to any chimeric analog. BIM23A761 activated c-Jun N-terminal kinase signaling and caused inhibition of Ki-67 transcription. P21WAF1/CIP1 transcription was activated only in NCI-H727 cells. CONCLUSIONS. The different responses of each individual cell line suggested that NETs from different locations arising from different neuroendocrine cells may require cell-specific antiproliferative agents based on the unique receptor profile of individual lesions. Cancer 2008. © 2008 American Cancer Society. [source] Geranylgeranylacetone inhibits lysophosphatidic acid-induced invasion of human ovarian carcinoma cells in vitroCANCER, Issue 7 2005Kae Hashimoto M.D. Abstract BACKGROUND Lysophosphatidic acid (LPA) induced a dose-dependent increase of cancer cell invasion by promoting Rho/Rho-associated kinase signaling. Prenylation of Rho is essential for regulating cell growth, motility, and invasion. Geranylgeranylacetone (GGA), an isoprenoid compound, is used clinically as an antiulcer drug. Recent findings suggested that GGA might inhibit the small GTPase activation by suppressing prenylation. The authors hypothesized that the anticancer effects of GGA result from the inhibition of Rho activation. METHODS The authors examined the effect of GGA using an in vitro invasion assay in human ovarian carcinoma cells, and analyzed the mechanism of the GGA effect on Rho activation, stress fiber formation and focal adhesion assembly, which are essential processes for cell invasion. RESULTS The induction of ovarian carcinoma cell invasion by LPA was inhibited by the addition of GGA in a dose-dependent manner. Treatment of cancer cells with GGA resulted in inactivation of Rho, changes in cell morphology, loss of stress fiber formation and focal adhesion assembly, and the suppression of tyrosine phosphorylation of focal adhesion proteins. The effect of GGA on cancer cells was partially prevented by the addition of geranylgeraniol, which is an intermediate of geranylgeranyl pyrophosphate and compensates geranylgeranylation of Rho. CONCLUSIONS The inhibition of LPA-induced invasion by GGA was, at least in part, derived from suppressed Rho activation by preventing geranylgeranylation. Cancer 2005. © 2005 American Cancer Society. [source] Simvastatin inactivates ,1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cellsCANCER SCIENCE, Issue 6 2007Ikuko Takeda The 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, also called statins, are commonly used as lipid-lowering drugs that inhibit cholesterol biosynthesis. An anticancer effect, as a pleiotropic function of certain statins, has been hypothesized. In the present study, we investigated the effect of simvastatin, one of the natural statins, on cell proliferation, cell cycle, invasive activity, and molecular expressions associated with cell,extracellular matrix adhesion, signal transduction, and DNA synthesis in Tu167 and JMAR cells from head and neck squamous cell carcinoma. The addition of simvastatin resulted in a dose-dependent inhibition of cell growth and migration into the extracellular matrix. Considerable morphological changes occurred after treatment with simvastatin, demonstrating loss of cell adhesion and disruption of actin filaments in cytoplasm. The inhibitory effect of simvastatin on cell proliferation seemed to be associated with cell cycle arrest and increased expression of p21, p27, and activated caspase-3. The expression of ,1-integrin, a counter adhesion for the extracellular matrix, phosphorylated FAK, and phosphorylated ERK was decreased by treatment with simvastatin. The proapoptotic effect of simvastatin was inhibited by treatment with mevalonate. cDNA microarray assay demonstrated that molecular changes resulting from treatment with simvastatin included the up-regulation of cell cycle regulators and apoptosis-inducing factors and the down-regulation of integrin-associated molecules and cell proliferation markers. Of down-regulated genes induced by simvastatin treatment, a significant depletion of thymidylate synthase was confirmed using western blot analysis. These results imply that simvastatin has the potential to be effective for the prevention of the growth and metastasis of cancer cells. (Cancer Sci 2007; 98: 890,899) [source] ETS transcription factors: Possible targets for cancer therapyCANCER SCIENCE, Issue 8 2004Tsuneyuki Oikawa Ets family (ETS) transcription factors, characterized by an evolutionally conserved Ets domain, play important roles in cell development, cell differentiation, cell proliferation, apoptosis and tissue remodeling. Most of them are downstream nuclear targets of Ras-MAP kinase signaling, and the deregulation of ETS genes results in the malignant transformation of cells. Several ETS genes are rearranged in human leukemia and Ewing tumors to produce chimeric oncoproteins. Furthermore, the aberrant expression of several ETS genes is often observed in various types of human malignant tumors. Considering that some ETS transcription factors are involved in malignant transformation and tumor progression, including invasion, metastasis and neo-angiogenesis through the activation of cancer-related genes, they could be potential molecular targets for selective cancer therapy. [source] | |||||||||||||