Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokine oncostatin M (OM) has profound effects on proliferation and differentiation of breast cancer cells. OM treated cells show reduced growth rate and differentiated phenotypes. The mechanisms underlying the OM growth-inhibitory activity in breast cancer cells have not been fully elucidated. In this study, we investigated the OM-elicited signaling pathways in breast cancer cell lines MDA-MB231 and MCF-7. We show that OM rapidly activates the extracellular signal-regulated kinase (ERK) and the signal transducer and activator of transcription (STAT) 1 and 3 in both cell lines. Intriguingly, OM-induced growth inhibition and morphological changes in MDA-MB231 cells are completely abolished by inhibitors to ERK upstream kinase MEK (nitrogen/extracellular-regulated protein kinase kinase), but the MEK inhibitors have little effects on OM growth-inhibitory activity in MCF-7 cells. In addition, expressions of the cyclin kinase inhibitors p21 and p27 are strongly induced by OM in MCF-7 cells, but their expression is only slightly increased by OM in MDA-MB231 cells. These data together demonstrate that the growth-inhibitory activity of OM can be mediated by different signaling pathways in a cell line-specific manner. While the MEK/ERK pathway is the predominant signaling pathway that leads to the growth inhibition of MDA-MB231 cells, activation of additional signaling pathways are necessary for OM to exert its growth-inhibitory activity in MCF-7 cells.
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PMID:Oncostatin M-induced growth inhibition and morphological changes of MDA-MB231 breast cancer cells are abolished by blocking the MEK/ERK signaling pathway. 1143 97

Replication-deficient adenoviruses expressing human interferon-alpha2b (HuIFN-alpha2b) or the hybrid IFN-alpha2alpha1 or those with the secretory signal deleted, whose express is driven by the alpha-fetoprotein (AFP) promoter, were constructed and characterized. Synthesis of IFN protein and secretion or intracellular retention were tested by Western blotting and immunoassay. Expression of IFN by the recombinant adenoviruses was restricted to cells that constitutively express AFP. In these cells, expression of both secreted and nonsecreted recombinant IFN resulted in inhibition of cell proliferation, resistance to viral infection, induction of major histocompatibility complex (MHC) class I expression, increased apoptosis, and activation of an IFN-stimulated response element (ISRE)-containing promoter. Also, the induction of protein kinase R (PKR), increased phosphorylation of Stat1, and accumulation of hypophosphorylated pRb were observed for both the secreted and nonsecreted IFN, suggesting that the nonsecreted IFN may act through a similar pathway. Hep3B cells, an AFP-positive line derived from a patient with hepatocellular carcinoma (HCC), were injected subcutaneously (s.c.) into athymic nude mice to generate established tumors. Intratumoral injection of recombinant adenoviruses expressing secreted as well as the nonsecreted IFN caused suppression of tumor growth. As the AFP promoter is activated in many HCC cells but is silent in normal cells, these constructs may be useful in restricting IFN effects to the tumor cells while reducing toxicity to the neighboring tissues.
J Interferon Cytokine Res 2001 Jun
PMID:Selective expression of nonsecreted interferon by an adenoviral vector confers antiproliferative and antiviral properties and causes reduction of tumor growth in nude mice. 1144 Jun 37

Interleukin 6 (IL-6) is the major survival factor of myeloma cells. In this study, we demonstrate that IL-6, oncostatin M (OSM) and leukemia inhibitory factor (LIF) upregulate membrane IL-6 receptor alpha (IL-6Ralpha) on OPM-2 myeloma cell line at transcriptional level. In OPM-2 cells, IL-6, OSM and LIF induce both signal transducers and activators of transcription (STAT), mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI 3-K) activation. We show that the cytokine-induced upregulation of IL-6Ralpha can be abolished by a janus kinase (JAK)-2 specific inhibitor, i.e. AG490, suggesting an involvement of the JAK/STAT pathway in this process. Finally, IL-6Ralpha upregulation was also inhibited by wortmannin, an inhibitor of the PI 3-kinase pathway. In conclusion, IL-6 can upregulate its own receptor on OPM-2 cells probably through the JAK/STAT and PI 3-kinase pathways.
Cytokine 2001 Jun 21
PMID:IL-6 upregulates its own receptor on some human myeloma cell lines. 1149 97

Thrombopoietin (TPO) plays a crucial role in megakaryocyte development. TPO signalling, which is mediated by its receptor Mpl, includes Janus kinase, (JAK) signal transducer and activator of transcription (STAT) and Shc/Ras/mitogen-activated protein kinase (MAPK) pathways. The precise nature of these signalling routes has not been clarified in detail up until now. We investigated the effect of TPO on activation of cAMP-dependent protein kinase (PKA) and its involvement in MAPK signalling in human megakaryoblastic leukaemia CMK cells. For estimation of PKA activity, phosphorylation of a PKA-specific peptide substrate was assayed in CMK cell lysates. Since activation of PKA is associated with translocation of its catalytic subunit alpha (C-PKA) into the cell nucleus, Western blot analysis of nuclear fractions with an anti-C-PKA antibody was additionally performed. The activation of TPO-induced MAPK activation and the effect of the PKA inhibitor H-89 was measured using immunoblotting with a monoclonal anti-pERK antibody. TPO enhanced cAMP and induced activation of PKA in CMK cells. In addition, H-89 partly blocked TPO-induced MAPK activation in CMK cells. Our results indicate a novel TPO-triggered signalling event, activation of the cAMP/PKA pathway in human megakaryoblastic CMK cells. This signal transduction route seems to be involved in TPO-induced MAPK signaling.
Cytokine 2001 Jul 21
PMID:Evidence for a novel thrombopoietin signalling event: activation of protein kinase A in human megakaryoblastic CMK cells. 1150 82

The PI3K/Akt and Raf/MEK/ERK signal transduction cascades are pivotal in transmitting signals from membrane receptors to downstream targets that regulate apoptosis, gene expression, and cell growth. The abilities of activated PI3K, Akt, Raf, and MEK proteins to abrogate the cytokine dependence of three different hematopoietic cell lines were determined. Activated PI3K or Akt expression by themselves did not efficiently annul cytokine dependence. Raf and MEK could abrogate the cytokine dependence of murine FDC-PI and human TF-1 cells; however, the frequency of transformation was dependent on the particular oncogene examined, as more factor-independent cells were isolated after infection with activated retroviruses encoding A-Raf or Raf-1 than were with MEK1 or B-Raf. Cytokine-independent deltaRaf-1-infected cells formed tumors on injection into immunocompromised mice, whereas cytokine-dependent cell lines did not, demonstrating the oncogenic effects of activation of the Raf/MEK/ERK pathway. Overexpression of the antiapoptotic Bcl-2 protein synergized with activation of the Raf/MEK/ERK cascade and increased the efficiency of transformation of FDC-PI and TF-1 cells. In contrast to the results observed with FDC-P1 and TF-I cells, the activated Raf genes did not relieve the cytokine dependence of murine FL5.12 cells. The abilities of the Raf and PI3K pathways to interact and annul the cytokine dependence of FL5.12 cells were determined. The combination of Raf and either PI3K or Akt expression relieved cytokine dependence of some FL5.12 cells, and the efficiency of transformation could be enhanced further by Bcl-2 or Bcl-XL overexpression. Thus, the antiapoptotic PI3K/Akt and Bcl-2/Bcl-XL proteins can interact with the growth-promoting Raf/MEK/ERK pathway and annul the cytokine dependence of certain hematopoietic cells.
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PMID:Interactions between the PI3K and Raf signaling pathways can result in the transformation of hematopoietic cells. 1153 Oct 15

Culture of an H-2(s)-restricted, bovine myelin basic protein (BMBP)-specific murine Th1 clone with the adenyl cyclase agonist forskolin (FSK) or isobutylmethylxanthine (IBMX), an inhibitor of cAMP catabolism, before culture with anti-CD3 or BMBP and antigen-presenting cells (APC) suppressed antigen or anti-CD3-induced proliferation and production of interferon-gamma (IFN-gamma). Other H-2(s)-derived or H-2(b)-derived clones specific for BMBP or keyhole limpet hemocyanin (KLH) were similarly affected. FSK did not affect the expression of CD4 or the T cell receptor (TCR) but did diminish levels of the phosphorylated (activated) mitogen-activated protein (MAP) kinases early response kinase-1 (ERK-1) and ERK-2. Immunoblotting of lysates from an FSK-treated Th1 clone with antibodies to a carboxy-terminal epitope of p56(lck), a signal transduction enzyme upstream from ERK-1 and ERK2, did not detect p56(lck) unless the lysates were reduced prior to electrophoresis. Immunoblotting of nonreduced lysates with antibodies to an amino-terminal epitope demonstrated p56(lck) with a lower apparent molecular weight, characteristic of oxidized proteins. Reduction restored the detection of p56(lck) by anticarboxy-terminal p56(lck) and to mobilities indistinguishable from controls detected by the antiamino-terminal p56(lck). N-acetylcysteine or catalase prevented FSK-induced suppression of antigen-induced proliferation and the loss of carboxy-terminal epitopes of p56(lck). An inhibitor of cAMP-dependent protein kinase A (PKA) or nitric oxide synthase (NOS) did not affect FSK-induced inhibition of antigen-induced proliferation. In contrast, inhibitors of PKA or NOS, but not catalase, prevented FSK-induced suppression of IFN-gamma production. Moreover, immunoblots of lysates precipitated with anti-p56(lck), phosphotyrosine, or CD4 demonstrated that in FSK-treated, anti-CD3-stimulated cells, p56(lck) is not associated with CD4 zeta chain, nor is p56(lck) or zeta chain phosphorylated. In vitro kinase assays demonstrated that p56(lck) from FSK-treated cells does not have kinase activity. Taken together, the results suggest that an elevation of intracellular cAMP (in the absence of antigen) creates an oxidative environment that oxidizes and inactivates p56(lck) by an H(2)O(2)-dependent, PKA-independent mechanism and inhibits the production of IFN-gamma by an NO, PKA-dependent mechanism. Thus, antigen-induced proliferation and IFN-gamma production in a Th1 clone are controlled separately by different cAMP-dependent, redox-based mechanisms.
J Interferon Cytokine Res 2001 Oct
PMID:Differential regulation of T cell receptor-mediated Th1 cell IFN-gamma production and proliferation by divergent cAMP-mediated redox pathways. 1171 Sep 91

Lipopolysaccharide (LPS) is a bacterial cell component that plays multifunctional roles in inflammatory reactions, and one of the roles is as a powerful stimulator of bone resorption. LPS stimulated bone resorption via CD14 in mouse calvaria and was reported to function as a receptor for bacterial LPS complexed with serum proteins. Interleukin-6 (IL-6) is capable of stimulating the differentiation of osteoclasts from their hematopoietic precursors, and LPS elevates IL-6 synthesis in human osteoblastic cells. However, the signaling pathway of LPS-induced IL-6 synthesis in osteoblasts is unknown. In the present study, we could detect the existence of CD14 in human osteoblastic cells by RT-PCR analysis and show that LPS increased IL-6 mRNA and synthesis via CD14 in human osteoblastic cells. In human osteoblasts (SaM-1 cells) treated with 10 microg/ml LPS, increases in IL-6 mRNA and synthesis were inhibited by anti-CD14 antibody (MEM-18), PD98059 (an inhibitor of classic mitogen-activated protein kinase [MAPK]), or SB203580 (an inhibitor of p38 MAPK) but were not inhibited by H-89 (an inhibitor of protein kinase A [PKA]) and calphostin C (an inhibitor of protein kinase C [PKC]). Furthermore, LPS-induced IL-6 synthesis was inhibited by curcumin (an inhibitor of activating protein-1 [AP-1]) but not by pyrrolidine dithiocarbamate (PDTC) (an inhibitor of nuclear factor kappa B [NF-kappaB]). The findings of the present study suggest that the LPS receptor CD14, existent in human osteoblastic cells, and IL-6 synthesis in response to LPS probably occur via CD14, p38 MAPK, and MAP kinase/extracellular-regulated kinase kinase (MEK), leading to the transcriptional activation of AP-1 in human osteoblastic cells.
J Interferon Cytokine Res 2001 Nov
PMID:Signal transduction system for interleukin-6 synthesis stimulated by lipopolysaccharide in human osteoblasts. 1174 26

The type I interferon-alpha (IFN-alpha) family is a family of natural small proteins that have clinically important anti-infective and antitumor activity. We have developed a semisynthetic protein-polymer conjugate of IFN-alpha2b (Intron A) by attaching a 12,000-Da monomethoxypolyethylene glycol (PEG-12000) polymer to the protein. PEG conjugation is thought to increase the serum half-life and thereby prolong patient exposure to IFN-alpha2b without altering the biologic potency to the protein. Matrix-assisted laser desorption ionization/mass spectrometry (MALDI-MS), high-performance size exclusion chromatography (HPSEC), circular dichroism (CD) analysis and tryptic digestion peptide analysis of PEG Intron demonstrated that the IFN-alpha2b protein was approximately 95% monopegylated and that the primary, the secondary, and the tertiary structures were unaltered. Pegylation did not affect the epitope recognition of antibodies used for Intron A quantitation. An extensive analysis of the pegylated positional isomers revealed that approximately 50% of PEG Intron was monopegylated on the His(34) residue of the IFN-alpha2b protein. The highest antiviral activity of the pegylated positional isomers for PEG Intron was associated with the His(34) pegylated isomer. The specific activity for PEG Intron in an antiviral cytopathic protection assay was 28%, relative to Intron A. However, the potency of PEG Intron, defined as bioactivity independent of protein concentration, was comparable to Intron A at both the molecular and cellular levels in a battery of in vitro assays. Equivalent units of PEG Intron and Intron A were indistinguishable for the induction of several key IFN-induced genes, including 2',5'-oligoadenylate synthetase (2',5'-OAS) and protein kinase R (PKR), in Molt 4 cells. The antiviral dose-response curves revealed that there were no significant differences between PEG Intron and Intron A. This demonstrated that the introduction of more IFN-alpha2b protein associated with equivalent unit dosing of PEG Intron did not create any antagonism or agonism in the antiviral assay. In assays for the immune response, PEG Intron and Intron A displayed comparable potency for both natural-killer (NK) and lymphokine-activated killer (LAK) cell cytolytic activity and for the induction of class I major histocompatibility protein. These results demonstrate that PEG Intron maintains an in vitro biologic potency profile for both antiviral and immunotherapeutic activity that is highly comparable to that of Intron A.
J Interferon Cytokine Res 2001 Dec
PMID:Structural and biologic characterization of pegylated recombinant IFN-alpha2b. 1179 69

We have recently shown that IL-10 represents an efficient stimulus for suppressor of cytokine signalling (SOCS)-3 mRNA expression in human neutrophils and PBMC. Herein, we identify cAMP-elevating agents such as prostaglandin E2 (PGE2), PGE1, forskolin, dibutyryl cAMP (dbcAMP) and cholera toxin as a novel class of agonists able to induce SOCS-3 mRNA and protein expression in human leukocytes, cooperating with interleukin-10 (IL-10) in such activities. While PGE2 or dbcAMP prolonged the stability of SOCS-3 mRNA isolated from IL-10-treated leukocytes, inhibitors of cAMP-dependent protein kinase A (H89, KT5720, and St-Ht31 peptide) did not influence the action of PGE2/dbcAMP and/or IL-10 on SOCS-3 mRNA and protein expression, implying that their effect are mediated through a PKA-independent pathway. Taken together, our data identify cAMP-elevating substances as a novel class of agonists able to trigger SOCS-3 expression, and suggest that SOCS-3 might be involved in the regulatory effects of cAMP-elevating substances.
Eur Cytokine Netw
PMID:Interleukin-10 and cAMP-elevating agents cooperate to induce suppressor of cytokine signaling-3 via a protein kinase A-independent signal. 1195 20

Cardiotrophin-1 (CT-1) is an Interleukin-6 family cytokine with known hypertrophic and protective effects in cardiac cells. CT-1 and the corticotrophin releasing hormone-like hormone urocortin protect cardiac myocytes by the same p42/44 mitogen activated protein kinase (p42/44 MAPK) dependent pathway. We investigated whether urocortin is also hypertrophic in cardiac myocytes and whether it shares a common pathway with CT-1 for this effect. Moreover, we also investigated, for the first time whether CT-1 and urocortin can induce hypertrophy in cultured adult as opposed to neonatal cardiac cells. Urocortin and CT-1 caused hypertrophy (as measured by an increase in cell area and enhanced protein: DNA ratio) in both adult and neonatal rat cultured cardiac myocytes. The hypertrophic effect of CT-1 was dependent on the signal transducer and activator of transcription 3 (STAT3) pathway but the hypertrophic effect of urocortin was independent of this pathway. In contrast, inhibition of the protective p42/p44 MAPK pathway has no effect on the hypertrophic effect of CT-1 or urocortin. Additionally, inhibition of the STAT3 pathway has no effect on the protective effect of CT-1 or urocortin. These results identify urocortin as a novel hypertrophic and protective agent whose hypertrophic effect is mediated by a distinct pathway to that activated by CT-1, although the two factors mediate protection via the same pathway.
Cytokine 2002 Mar 07
PMID:Cardiotrophin-1 and urocortin cause protection by the same pathway and hypertrophy via distinct pathways in cardiac myocytes. 1202 5


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