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The stress-activated protein kinase pathways 总被引:29,自引:0,他引:29
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Silberman DM Zorrilla-Zubilete M Cremaschi GA Genaro AM 《Cellular and molecular life sciences : CMLS》2005,62(15):1744-1754
Chronic stress has been associated with impaired immune function. In this work we studied the effect of chronic mild stress (CMS) exposure on the early intracellular pathways involved in T cells after stimulation with mitogen. We found that mitogen stimulation of T lymphocytes from CMS-exposed mice resulted in a reduction of the intracellular [Ca2+] rise, an impairment of growth-promoting protein kinase C (PKC) activation, a lower NF-κB activation and an increase in the inhibitory cAMP-protein kinase A (PKA) pathway activity with respect to those found in control lymphocytes. However, T cell activation with the direct PKC activator phorbol 12-myristate 13-acetate plus calcium ionophore led to a similar proliferative response in both CMS and control lymphocytes, indicating that signals downstream of PKC would not be affected by stress. In summary, our results show that chronic stress induced an alteration in T cell early transduction signals that result in an impairment of the proliferative response.Received 11 February 2005; received after revision 20 May 2005; accepted 6 June 2005 相似文献
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Bartolomé F de Las Cuevas N Muñoz U Bermejo F Martín-Requero A 《Cellular and molecular life sciences : CMLS》2007,64(11):1437-1448
We have analyzed the intracellular signals that allow lymphoblasts from Alzheimer’s disease (AD) patients to escape from serum
deprivation-induced apoptosis. The following observations suggested that modulation of ERK1/2 activity by Ca2+/calmodulin (CaM) is involved in preventing apoptosis: (i) ERK1/2 activity seems to support lethality in control cells, as
PD98059, the inhibitor of the activating MEK prevented cell death; (ii) control cells show a persistent and higher stimulation
of ERK1/2 than that of AD cells in the absence of serum; (iii) CaM antagonists have no effects on control cells, but sensitize
AD cells to death induced by serum withdrawal and increased ERK1/2 phosphorylation, and (iv) no apoptotic effects of CaM antagonists
were observed in AD cells treated with PD98059. These results suggest the existence of an activation threshold of the ERK1/2
pathway setting by Ca2+/CaM-dependent mechanisms, which appears to be the critical factor controlling cell survival or death decision under trophic
factor withdrawal.
F. Bartolomé, N. de las Cuevas: These authors contributed equally to this work.
Received 14 February 2007; received after revision 16 April 2007; accepted 23 April 2007 相似文献
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ERKs are the point of divergence of PKA and PKC activation by PTHrP in human skin fibroblasts 总被引:3,自引:0,他引:3
Fortino V Torricelli C Gardi C Valacchi G Rossi Paccani S Maioli E 《Cellular and molecular life sciences : CMLS》2002,59(12):2165-2171
Parathyroid hormone-related peptide (PTHrP) receptors, coupled to trimeric G proteins, operate in most target cells through
at least three different transduction routes: Gαs-mediated stimulation of adenylylcyclase (AC), Gαq-mediated activation of
phospholipase Cβ (PLC) and mitogen-activated protein kinase (MAPK) activation. In this study we investigated the relative
role of different pathways in human skin fibroblast prolifera-tion. Using chemical inhibitors and activators of signal transduction,
we demonstrated that: (i) AC/cAMP and PLC/1,4,5 inositol triphosphate/diacylglycerol second-messenger systems are simultaneously
activated following PTHrP binding to its receptors; (ii) the mitogenic response to PTHrP derives from a balance between two
counteracting pathways – an activating route mediated by protein kinase C (PKC) and an inhibitory route mediated by protein
kinase A (PKA); (iii) PTHrP mitogenic effects are largely dependent on MAPKs, whose activity can be modulate
d by both PKA and PKC. Our results indicate that MAPKs are common targets of both transduction routes and, at the same time,
their point of divergence in mediating PTHrP dual and opposite mitogenic effects.
Received 2 August 2002; received after revision 10 September 2002; accepted 18 October 2002
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ID="*"Corresponding author. 相似文献
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The intracellular signaling pathways mediating the nuclear exclusion of the androgen receptor (AR) by melatonin were evaluated
in PC3 cells stably transfected with the AR. The melatonin-induced nuclear exclusion of the AR by melatonin (100 nM, 3 h)
was blocked by LY 83583 (an inhibitor of guanylyl cyclases). 8-Bromo-cGMP (a cell-permeable cGMP analog), mimicked the effect
of melatonin, as did ionomycin (a calcium ionophore) and PMA [an activator of protein kinase C (PKC)], and their effects were
blocked by GF-109203X (a selective PKC inhibitor). BAPTA (an intracellular calcium chelator) blocked the effects of melatonin
and 8-bromo-cGMP but not of PMA. Inhibition or activation of the protein kinase A pathway did not affect basal or melatonin-mediated
AR localization. We conclude that the melatonin-mediated rise in cGMP elicits AR nuclear exclusion via a pathway involving
increased intracellular calcium and PKC activation. These results define a novel signaling pathway that regulates AR localization
and androgen responses in target cells.
Received 31 July 2001; received after revision 18 September 2001; accepted 30 October 2001 相似文献
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Cell motility is defined as cell movement in the three-dimensional space leading to repositioning of the cell. Atypical protein kinase C (aPKC, including ζ and λ/ι) are a subfamily of PKC. Different from classic PKC and novel PKC, the activation of atypical PKC is not dependent on diacylglycerol or calcium. PKCζ can be activated by lipid components, such as phosphatidylinositols, phosphatidic acid, arachidonic acid, and ceramide. Both phosphatidylinositol (3,4,5)-trisphosphate and PDK1 are necessary for the complete and stable activation of PKCζ. Atypical PKC is involved in the regulation of cell polarization, directional sensing, formation of filopodia, and cell motility. It is essential for migration and invasion of multiple cancer cell types. Particularly, atypical PKC has been found in the regulation of the motility of hematopoietic cells. It also participates in the regulation of proteolytic activity of podosomes and invadopodia. It has been found that atypical PKC can work coordinately with other PKC subfamily members and other signaling pathways. Research on the roles of atypical PKC in cell motility may lead to new therapeutic strategies for cancer and other diseases. 相似文献
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Arachiche A Badirou I Dachary-Prigent J Garcin I Geldwerth-Feniger D Kerbiriou-Nabias D 《Cellular and molecular life sciences : CMLS》2008,65(23):3861-3871
Rapid Ca2+-dependent phospholipid (PL) reorganization (scrambling) at the plasma membrane is a mechanism common to hematopoietic cells
exposing procoagulant phosphatidylserine (PS). The aim of this research was to determine whether activation of the extracellular
signal-regulated kinase (ERK) pathway was required for PL scrambling, based on a single report analyzing both responses induced
by Ca2+ ionophores in megakaryoblastic HEL cells. Ca2+ ionophore-stimulated ERK phosphorylation was induced in platelets without external Ca2+, whereas exogenous Ca2+ entry was crucial for ERK activation in Jurkat T cells. In both cells, membrane scrambling only occurred following Ca2+ entry and was not blocked by inhibiting ERK phosphorylation. Furthermore, ERK proteins are strongly phosphorylated in transformed
B lymphoblastic cell lines, which do not expose PS in their resting state. Overall, the data demonstrated that ERK activation
and membrane scrambling are independent mechanisms.
A. Arachiche, I. Badirou: These authors contributed equally to this work.
Received 18 June 2008; received after revision 24 September 2008; accepted 1 October 2008 相似文献
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An increase in mouse cerebellar C-GMP levels during acute morphine treatment was observed, which was possibly related to the decrease in C-GMP phosphodiesterase levels also observed in acute treatment. Chronic treatment lowered C-GMP levels as did abrupt withdrawal without naloxone. 相似文献
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Summary An increase in mouse cerebellar C-GMP levels, during acute morphine treatment was observed, which was possibly related to the decrease in C-GMP phosphodiesterase levels also observed in acute treatment. Chronic treatment lowered C-GMP levels as did abrupt withdrawal without naloxone. 相似文献
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Mijatovic S Maksimovic-Ivanic D Radovic J Miljkovic D Kaludjerovic GN Sabo TJ Trajkovic V 《Cellular and molecular life sciences : CMLS》2005,62(11):1275-1282
The present study describes the ability of an anthraquinone derivative aloe emodin (AE) to reduce the cytotoxic activity of the platinum(II)-based anticancer agent cisplatin toward murine L929 fibrosarcoma and C6 glioma cell lines. The protective effect of AE was demonstrated by MTT and crystal violet assays for cell viability, and involved supression of cisplatin-induced apoptosis and necrosis, as assessed by lactate dehydrogenase release and flow cytometric analysis of DNA fragmentation or phosphatidylserine exposure. Cell-based ELISA and Western blot analysis revealed that AE abolished cisplatin-triggered activation of extracellular signal-regulated kinase (ERK) in tumor cells, while activation of c-Jun N-terminal kinase was not significantly altered. A selective blockade of ERK activation with PD98059 mimicked the protective effect of AE treatment in both tumor cell lines. Moreover, AE failed to protect tumor cells against the ERK-independent toxicity of the Pt(IV)-based complex tetrachloro(O,O-dibutyl-ethylenediamine-N,N′-di-3-propanoate)platinum(IV). Taken together, these data indicate that herbal anthraquinone AE can downregulate the anticancer activity of cisplatin by blocking the activation of ERK in tumor cells.Received 30 January 2005; received after revision 21 March 2005; accepted 31 March 2005 相似文献
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Protein kinases: which one is the memory molecule? 总被引:12,自引:0,他引:12
Encoding of new experiences is likely to induce activity-dependent modifications in the brain. Studies in organisms far apart
on the phylogenetic scale have shown that similar, sometimes identical, signal transduction pathways subserve plasticity in
neuronal systems, and they may play pivotal roles in the formation of long-term memories. It has become evident that phosphorylation/dephosphorylation
reactions are critical for the initiation of cellular mechanisms that embody, retain and modify information in neural circuits.
Although physiological investigations on synaptic plasticity have had a major impact, we have concentrated our review on behavioural
studies that provide direct or indirect evidence for a role of kinases in mechanisms underlying memory formation. From these,
it appears that the learning event induces activation of a variety of kinases with specific time courses. For instance, the
calcium/calmodulin-dependent protein kinase II seems to participate in an early phase of memory formation. Apparently, activation
of both protein tyrosine kinases and mitogen-activated protein kinases is required for much longer and may thus have a particular
function during transformation from short-term into long-term memory. Quite different time courses appear for protein kinase
C (PKC) and protein kinase A (PKA), which may function at two different time points, shortly after training and again much
later. This suggests that PKC and PKA might play a role at early and late stages of memory formation. However, we have considered
some examples showing that these signalling pathways do not function in isolation but rather interact in an intricate intracellular
network. This is indicative of a more complex contribution of each kinase to the fine tuning of encoding and information processing.
To decipher this complexity, pharmacological, biochemical and genetic investigations are more than ever necessary to unravel
the role of each kinase in the syntax of learning and memory formation. 相似文献
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K. Blum J. E. Wallace H. A. Schwerter J. D. Eubanks 《Cellular and molecular life sciences : CMLS》1976,32(1):79-82
Summary The acute administration of morphine, alcohol or dopamine results in a pronounced suppression of the convulsions produced by alcohol in mice. The suppressive action of morphine on alcohol withdrawal in the mouse apparently is not a product of morphine intoxication, but rather to some other specific interaction between alcohol and morphine in the central nervous system. The conclusion suggest that dopamine may play a significant role as a modulator in convulsions produced during alcohol withdrawal.Dr.Kenneth Blum is Associate Professor in Pharmacology at The University of Texas Health Science Center at San Antonio and a Career Teacher in Drug Abuse and Alcoholism under a grant number 1-TO1-DA00290-01 from the National Institute on Drug Abuse.Acknowledgments. Our thanks are due toB. Wiggins, R. Marin andS. Elston for their excellent technical assistance. Research funded in part by Air Force Grant No. AFOSR-71-2075. 相似文献
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Mohammed I Yeung A Abedin A Hopkinson A Dua HS 《Cellular and molecular life sciences : CMLS》2011,68(11):1941-1952
Antimicrobial peptides are host defence molecules that play a potential role in preventing infection at the epithelial surfaces.
Ribonuclease (RNase)-7 has been shown to possess a broad spectrum of microbicidal activity against various pathogens. Here,
we demonstrate that RNase-7 protein is localised to the superficial layers of ocular surface cells and increased in response
to interleukin (IL)-1β, suggesting an active role during inflammation related to ocular surface infection. Signal transduction
pathways involved in RNase-7 expression are unknown. Involvement of transforming growth factor β-activated kinase-1 (TAK-1)
activated nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathway molecules [c-Jun N-terminal kinase
(JNK), extracellular signal-regulated kinase (ERK) and p38] were studied because of their importance in infection and inflammation.
Blocking the MAPKs resulted in inhibition of RNase-7 expression in response to IL-1β. However, RNase-7 induction by IL-1β
was not affected by inhibiting the NF-κB signalling pathway. In conclusion, our results indicate that RNase-7 expression is
specifically mediated via MAPKs but not NF-κB signalling pathways. 相似文献
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Julhash U. Kazi Rohit A. Chougule Tianfeng Li Xianwei Su Sausan A. Moharram Kaja Rupar Alissa Marhäll Mohiuddin Gazi Jianmin Sun Hui Zhao Lars Rönnstrand 《Cellular and molecular life sciences : CMLS》2017,74(14):2679-2688
The type III receptor tyrosine kinase FLT3 is frequently mutated in acute myeloid leukemia. Oncogenic FLT3 mutants display constitutive activity leading to aberrant cell proliferation and survival. Phosphorylation on several critical tyrosine residues is known to be essential for FLT3 signaling. Among these tyrosine residues, Y842 is located in the so-called activation loop. The position of this tyrosine residue is well conserved in all receptor tyrosine kinases. It has been reported that phosphorylation of the activation loop tyrosine is critical for catalytic activity for some but not all receptor tyrosine kinases. The role of Y842 residue in FLT3 signaling has not yet been studied. In this report, we show that Y842 is not important for FLT3 activation or ubiquitination but plays a critical role in regulating signaling downstream of the receptor as well as controlling receptor stability. We found that mutation of Y842 in the FLT3-ITD oncogenic mutant background reduced cell viability and increased apoptosis. Furthermore, the introduction of the Y842 mutation in the FLT3-ITD background led to a dramatic reduction in in vitro colony forming capacity. Additionally, mice injected with cells expressing FLT3-ITD/Y842F displayed a significant delay in tumor formation, compared to FLT3-ITD expressing cells. Microarray analysis comparing gene expression regulated by FLT3-ITD versus FLT3-ITD/Y842F demonstrated that mutation of Y842 causes suppression of anti-apoptotic genes. Furthermore, we showed that cells expressing FLT3-ITD/Y842F display impaired activity of the RAS/ERK pathway due to reduced interaction between FLT3 and SHP2 leading to reduced SHP2 activation. Thus, we suggest that Y842 is critical for FLT3-mediated RAS/ERK signaling and cellular transformation. 相似文献
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Smith NJ Chan HW Osborne JE Thomas WG Hannan RD 《Cellular and molecular life sciences : CMLS》2004,61(21):2695-2703
Activation of the type 1 angiotensin II receptor (AT(1)R) is associated with the aetiology of left ventricular hypertrophy, although the exact intracellular signalling mechanism(s) remain unclear. Transactivation of the epidermal growth factor receptor (EGFR) has emerged as a central mechanism by which the G protein-coupled AT(1)R, which lacks intrinsic tyrosine kinase activity, can stimulate the mitogen-activated protein kinase signalling pathways thought to mediate cardiac hypertrophy. Current studies support a model whereby AT(1)R-dependent transactivation of EGFRs on cardiomyocytes involves stimulation of membrane-bound metalloproteases, which in turn cleave EGFR ligands such as heparin-binding EGF from a plasma membrane-associated precursor. Numerous aspects of the 'triple membrane-passing signalling' paradigm of AT(1)R-induced EGFR transactivation remain to be characterised, including the identity of the specific metalloproteases involved, the intracellular mechanism for their activation and the exact EGFR subtypes required. Here we examine how 'hijacking' of the EGFR might explain the ability of the AT(1)R to elicit the temporally and qualitatively diverse responses characteristic of the hypertrophic phenotype, and discuss the ramifications of delineating these pathways for the development of new therapeutic strategies to combat cardiac hypertrophy. 相似文献
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TRAIL promotes the survival,migration and proliferation of vascular smooth muscle cells 总被引:4,自引:0,他引:4
Secchiero P Zerbinati C Rimondi E Corallini F Milani D Grill V Forti G Capitani S Zauli G 《Cellular and molecular life sciences : CMLS》2004,61(15):1965-1974
Human and rat primary sub-cultured vascular smooth muscle cells (VSMCs) showed clear expression of the
death receptors TRAIL-R1 and TRAIL-R2; however, recombinant soluble TRAIL did not induce cell death when added to
these cells. TRAIL tended to protect rat VSMCs from apoptosis induced either by inflammatory cytokines tumor
necrosis factor- + interleukin-1 + interferon- or by prolonged serum withdrawal, and promoted a
significant increase in VSMC proliferation and migration. Of note, all the biological effects induced by TRAIL
were significantly inhibited by pharmacological inhibitors of the ERK pathway. Western blot analysis consistently
showed that TRAIL induced a significant activation of ERK1/2, and a much weaker phosphorylation of Akt, while it
did not affect the p38/MAPK pathway. Taken together, these data strengthen the notion that the TRAIL/TRAIL-R
system likely plays a role in the biology of the vascular system by affecting the survival, migration and
proliferation of VSMCs.Received 6 May 2004; received after revision 7 June 2004; accepted 8 June 2004 相似文献