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At least 577 records · Page 32Linked to original sources
PubMed2004

Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo?

Reactive gliosis is a hallmark of disease-, trauma-, and chemical-induced damage to the central nervous system. The signaling pathways associated with this response to neural injury remain to be elucidated, but recent evidence implicates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. Here, we used the known dopaminergic neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to selectively damage striatal dopaminergic nerve terminals and elicit a glial response. We then analyzed changes in gene expression and protein phosphorylation, in vivo, to identify ligands and mediators of the JAK-STAT pathway that accompany glial activation. Administration of MPTP caused rapid tyrosine (Tyr-705) phosphorylation and nuclear translocation of STAT3 in striatal astrocytes, prior to the induction of glial fibrillary acidic protein mRNA and protein. Pharmacological protection of dopaminergic nerve terminals with nomifensine abolished MPTP-mediated phosphorylation and translocation of STAT3 and prevented induction of astrogliosis. Among the Janus kinase family of tyrosine kinases, only JAK2 was associated with the phosphorylation of STAT3 after MPTP and, inhibition of JAK2 by AG490, in vivo, attenuated both the phosphorylation of STAT3 and induction of GFAP. The p44/42 mitogen-activated protein kinase (MAPK; ERK1/2) also was activated by MPTP, but was not associated with activation of STAT3, because serine (Ser-727) was not phosphorylated. The mRNA for ligands of the gp130-JAK/STAT3 signaling pathway, interleukin-6, leukemia inhibitory factor, and oncostatin M were elevated prior to activation of STAT3 and induction of astrogliosis; neuroprotection with nomifensine blocked these effects of MPTP. Taken together, our results suggest that the gp130-mediated activation of JAK2/STAT3 signaling pathway may play a key role in the induction of astrogliosis.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Two cAMP receptors activate common signaling pathways in Dictyostelium.

Multiple signal transduction pathways within a single cell may share common components. In particular, seven different transmembrane helix receptors may activate identical pathways by interacting with the same G-proteins. Dictyostelium cells respond to cAMP using one such receptor, cAR1, coupled by a typical heterotrimeric G-protein to intracellular effectors. However, cells in which the gene for cAR1 has been deleted are unexpectedly still able to respond to cAMP. This implies either that certain responses are mediated by a different receptor than cAR1, or alternatively that a second, partially redundant receptor shares some of the functions of cAR1. We have examined the dose response and ligand specificity of one response, cAMP relay, and the dose response of another, cyclic GMP synthesis. In each case, the EC50 was approximately 100-fold higher and the maximal response was smaller in car1- than wild-type cells. These data indicate that cAR1 normally mediates responses to cAMP. The ligand specificity suggests that the responses seen in car1- mutants are mediated by a second receptor, cAR3. To test this hypothesis, we constructed a cell line containing deletions of both cAR1 and cAR3 genes. As predicted, these lines are totally insensitive to cAMP. We conclude that the functions of the cAR1 and cAR3 receptors are partially redundant and that both interact with the same heterotrimeric G-protein to mediate these and other responses.

Adenylyl Cyclases↗
PubMedDate not supplied

Asbestos-induced activation of cell signaling pathways in human bronchial epithelial cells.

Using respiratory epithelial cells transfected with either superoxide dismutase (SOD) or catalase, the authors tested the hypothesis that the activation of the epidermal growth factor (EGF) receptor signal pathway after asbestos exposure involves an oxidative stress. Western blotting using phospho-specific antibodies demonstrated that the EGF receptor kinase inhibitor PD153035 decreased both the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and its upstream signal pathway, including mitogen-activate protein kinase/ERK kinase (MEK)1/2. Similarly, the MEK1/2 kinase inhibitor PD98059 also demonstrated the ability to decrease phosphorylation of ERK1/2. Crocidolite-induced phosphorylation of EGF receptor, ERK1/2, and MEK1/2 was reduced by transfection of BEAS-2B cells with a catalase vector, supporting a participation of oxidative stress in this pathway. These results show that crocidolite can activate the phosphorylation of EGF receptor and its downstream cell signal pathway in BEAS-2B cells and this is associated with the oxidative stress presented by the fibers.

Asbestos, Crocidolite↗
PubMedDate not supplied

Role of the p38 MAP-kinase signaling pathway for Cx32 and claudin-1 in the rat liver.

Liver regeneration and cholestasis are associated with adaptive changes in expression of gap and tight junctions through signal transduction. The roles of stress responsitive MAP-kinase, p38 MAP-kinase, in the signaling pathway for gap junction protein, Cx32, and tight junction protein, claudin-1, were examined in rat liver in vivo and in vitro, including regeneration following partial hepatectomy and cholestasis after common bile duct ligation. Changes in the expression and function of Cx32 and claudin-1 in hepatocytes in vivo were studied using the p38 MAP-kinase inhibitor SB203580. Following partial hepatectomy and common bile duct ligation, down-regulation of Cx32 protein was inhibited by SB203580 treatment. Up-regulation of claudin-1 protein was enhanced by SB203580 treatment after partial hepatectomy but not common bile duct ligation. However, no change of the Ki-67 labeling index (which is a marker for cell proliferation) in the livers treated with SB203580, was observed compared to that without SB203580 treatment. In primary cultures of rat hepatocytes, however, treatment with a p38 MAP-kinase activator, anisomycin, decreased Cx32 and claudin-1 protein levels. p38 MAP-kinase may be an important signaling pathway for regulation of gap and tight junctions in hepatocytes. Changes of gap and tight junctions during liver regeneration and cholestasis are shown to be in part controlled via the p38 MAP-kinase signaling pathway and are independent of cell growth.

Animals↗
PubMed1999

Negative regulation of N-cadherin-mediated cell-cell adhesion by the estrogen receptor signaling pathway in rat pituitary GH3 cells.

The ability of the estrogen receptor signaling pathway to regulate cell-cell adhesion, and N-cadherin and beta-catenin expression was examined in rat somatolactotropic GH3 cells cultured in serum-free, phenol red-free medium (SFM). Estradiol-17beta (E2) promoted a nonadherent phenotype, whereas the steroidal antiestrogen, ICI 182,780, induced the formation of tightly adherent aggregates of cells. The antiestrogen-induced cell-cell adhesion was associated with the presence of adherens junctions, and was Ca2+-dependent. E2 reduced surface N-cadherin protein to barely detectable levels, whereas ICI 182,780-treated cells displayed abundant punctate immunoreactive N-cadherin. Antiestrogen failed to induce adhesion in the presence of a blocking antibody to N-cadherin. ICI 182,780 increased the protein levels for N-cadherin and the cadherin-binding protein, beta-catenin, by twofold over SFM controls or E2-treated samples. ICI 182,780 also increased the mRNA levels for N-cadherin and beta-catenin by two- to fivefold. In GH3 cells cultured in growth medium, ICI 182,780 increased N-cadherin and beta-catenin levels by twofold over untreated controls, and inhibited cell proliferation by 53%. These results provide the first demonstration of the regulation of N-cadherin-mediated cell-cell adhesion by the estrogen receptor (ER) signaling pathway in pituitary somatolactotrophs through the coordinate regulation of N-cadherin and beta-catenin expression. The inverse relationship between ICI 182,780-induced adhesion and proliferation raises the possibility that these two processes are functionally related.

Animals↗
PubMed2003

A3 adenosine and CB1 receptors activate a PKC-sensitive Cl- current in human nonpigmented ciliary epithelial cells via a G beta gamma-coupled MAPK signaling pathway.

(1) We examined A3 adenosine and CB1 cannabinoid receptor-coupled signaling pathways regulating Cl(-) current in a human nonpigmented ciliary epithelial (NPCE) cell line. (2) Whole-cell patch-clamp recordings demonstrated that the A3 receptor agonist, IB-MECA, activates an outwardly rectifying Cl(-)current (I(Cl,Aden)) in NPCE cells, which was inhibited by the adenosine receptor antagonist, CGS-15943 or by the protein kinase C (PKC) activator, phorbol 12,13 dibutyrate (PDBu). (3) Treatment of NPCE cells with pertussis-toxin (PTX), or transfection with the COOH-terminus of beta-adrenergic receptor kinase (ct-betaARK), inhibited I(Cl,Aden). The phosphatidyl inositol 3-kinase (PI3K) inhibitor, wortmannin, had no effect on I(Cl,Aden); however, the mitogen-activated protein kinase kinase (MEK) inhibitor, PD98059, inhibited I(Cl,Aden). (4) Reverse transcription-polymerase chain reaction experiments and immunocytochemistry confirmed mRNA and protein expression for the CB1 receptor in NPCE cells, and the CB1 receptor agonist, Win 55,212-2, activated a PDBu-sensitive Cl(-) current (I(Cl,Win)). (5) Transfection of NPCE cells with the human CB1 (hCB1) receptor, increased I(Cl,Win), consistent with increased receptor expression, and I(Cl,Win) in hCB1 receptor-transfected cells was decreased after application of a CB1 receptor inverse agonist, SR 141716. (6) Constitutive activity for CB1 receptors was not significant in NPCE cells as transfection with hCB1 receptors did not increase basal Cl(-) current, nor was basal current inhibited by SR 141716. (7) I(Cl,Win) was inhibited by PTX preincubation, by transfection with ct-betaARK and by the MEK inhibitor, PD98059, but unaffected by the PI3K inhibitor, wortmannin. (8) We conclude that both A3 and CB1 receptors activate a PKC-sensitive Cl(-) current in human NPCE cells via a G(i/o)/Gbetagamma signaling pathway, in a manner independent of PI3K but involving MAPK.

Cell Line, Transformed↗
PubMed1996

Stimulation of the P-450 side chain cleavage enzyme (CYP11A1) promoter through ras- and Ets-2-signaling pathways.

Expression of the ovine P-450 side-chain cleavage enzyme gene (CYP11A1) is stimulated by epidermal growth factor (EGF) through a pathway that involves c-Jun in JEG-3 placental cells. Growth factor signaling involves ras-dependent and ras-independent signaling pathways, which in turn regulate gene transcription through related but distinct mitogen-activated protein kinase pathways (MAPKs) including the extracellular signal-regulated kinases (ERKs) and the stress-activated protein kinases (SAPKs). We investigated the intracellular signaling pathways governing EGF induction of the CYP11A1 promoter. EGF stimulation of the CYP11A1 promoter (4-fold) was reduced 60% by a dominant negative mutant of ras (N17), and 30-40% by antisense ras. EGF induced both ERK and SAPK activity in JEG-3 cells. EGF-induced CYP11A1 promoter activity was reduced 60% by the MEK1 inhibitor PD098059 and 50% by a dominant negative mutant of the ERK-specific regulator MEK1. In contrast, dominant negative mutants of the SAPK-specific activator, SEK1, induced a further increase in EGF-induced CYP11A1 promoter activity. Constitutively active mutants of ras (V12 or L61) increased CYP11A1 promoter activity 6- to 8-fold. Deletion of the EGF response element (EGF-RE) between -92 and -77 bp reduced ras induction by 60%; however, a residual 3-fold induction remained through the proximal -77 bp. Mutation of the EGF-RE AP-1-like sequence in the context of the native promoter reduced CYP11A1 promoter activation by ras 60%. The EGF-RE sequence was sufficient for 6-fold activation by ras in the context of an heterologous thymidine kinase promoter. Candidate transcription factor targets (c-Jun, c-Ets-2) for the ras-signaling cascade were examined for their effects on CYP11A1 promoter activity. Overexpression of c-Jun induced the CYP11A1 promoter through the EGF-RE; however, c-Ets-2 activation of the CYP11A1 promoter (12-fold) required the proximal ras-responsive promoter sequences that are distinct from the EGF/MEK/c-Jun-responsive element. Induction of the CYP11A1 promoter by EGF involves a ras/MEK1/AP-1-dependent pathway that is distinct from induction by ras/c-Ets-2.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed2005

Cross-talk between IGF-I and TGF-beta signaling pathways.

Insulin-like growth factor-I (IGF-I) has gained broad recognition as an important survival factor for epithelial cells in numerous tissues. The IGF-I receptor signaling pathway is deregulated in the majority of carcinomas, and such deregulation has also been reported to be tightly associated with enhanced tumor progression and metastasis. One of the key proteins that transduces IGF-I signals and is phospho-activated downstream of the IGF-I receptor, is the non-receptor serine/threonine kinase proto-oncogene protein kinase B (PKB, also known as Akt). This kinase serves as a major molecular node to control the function of many cell survival and death proteins through phosphorylation-mediated protein modification. The end result of the activation of Akt is enhanced cell survival and proliferation, pre-requisites for malignant transformation. Recent studies show that IGF-I signals cross-talk at multiple levels with various components of the TGF-beta signaling pathway, which depending on context may function either as tumor suppressor or as tumor promoter. Thus, a better understanding of how the IGF-I and TGF-beta signaling pathways are mutually interconnected is likely to unveil novel targets for the therapeutic intervention of many cancers.

Animals↗
PubMed2003

Extracellular calcium is a potent inducer of cyclo-oxygenase-2 in murine osteoblasts through an ERK signaling pathway.

UNLABELLED: [Ca2+]e may be important in bone turnover. We found [Ca2+]e induces COX-2 transcription and PGE2 production in primary calvarial osteoblasts through an ERK signaling pathway. Inhibition of PGE2 production inhibited the [Ca2+]e stimulation of osteoblastic differentiation but not the increase in cell number. Hence, some effects of [Ca2+]e on bone may be mediated by COX-2. INTRODUCTION: Local changes in extracellular calcium ([Ca2+]e) may play an important role in bone turnover. We examined the possibility that prostaglandins produced by cyclo-oxygenase-2 (COX-2) could mediate some of the effects of [Ca2+]e on osteoblasts. METHODS: We examined the [Ca2+]e induction of COX-2 expression and prostaglandin E2 (PGE2) production in primary osteoblasts (POBs) obtained by sequential enzymatic digestion of mouse calvariae. We measured mRNA and protein levels by Northern and Western analyses and PGE2 production in culture medium by radioimmunoassay (RIA). COX-2 promoter activity was measured as luciferase activity in calvarial osteoblasts derived from mice transgenic for 371 bp of the COX-2 promoter fused to a luciferase reporter gene. RESULTS AND CONCLUSIONS: COX-2 mRNA and protein expression were induced by 3-40 mM of [Ca2+]e. [Ca2+]e (5 mM) induced COX-2 mRNA within 30 minutes; levels peaked at 6-9 h and remained elevated at 24 h. Cumulative medium PGE2 was increased at 3 h, with levels rising to 30 nM at 24 h. PGE2 production in POBs from mice with only COX-1 gene expression was 1/40th of that in POBs from mice with both COX-1 and COX-2 gene expression. [Ca2+]e increased alkaline phosphatase activity and osteocalcin mRNA, and this increase was blocked by inhibiting PGE2 production. [Ca2+]e stimulation of COX-2 promoter activity correlated with the induction of COX-2 mRNA expression. [Ca2+]e induced rapid and transient phosphorylation of extracellular signal-regulated kinase (ERK) in POBs, which peaked at 5-10 minutes. Inhibition of ERK phosphorylation with the specific inhibitors, PD-98059 and U-0126, decreased the [Ca2+]e induction of both COX-2 mRNA and luciferase activity by 70-80%. Although less effective than [Ca2+]e, strontium [Sr2+]e also induced COX-2 mRNA and promoter activity in POBs through an ERK signaling pathway. We conclude that [Ca2+]e is a potent transcriptional inducer of COX-2 expression and PGE2 production in osteoblasts through an ERK signaling pathway.

Alkaline Phosphatase↗
PubMed2006

Leptin regulates neointima formation after arterial injury through mechanisms independent of blood pressure and the leptin receptor/STAT3 signaling pathways involved in energy balance.

BACKGROUND: Leptin is an adipocyte-derived hormone critical for energy homeostasis and implicated in vascular disease processes. The relevant cellular leptin receptor pools and signaling pathways involved in leptin-related vascular phenotypes in vivo are unclear. METHODS AND RESULTS: Arterial injury was induced in wild-type (wt), leptin-deficient (lep(ob/ob)), and leptin receptor-deficient (lepr(db/db)) mice. Compared with wt mice, lep(ob/ob) and lepr(db/db) mice were protected from the development of neointima. Bone marrow transplantation experiments between wt and lepr(db/db) mice indicated that the vascular protection in lepr(db/db) mice was not attributable to lack of leptin receptor expression on bone marrow-derived elements. To investigate the role of the lepr-mediated signal transducer and activator of transcription 3 (STAT3) signaling pathway in the response to vascular injury, lepr(s/s) mice homozygous for a leptin receptor defective in STAT3 signaling underwent femoral arterial injury. Despite similar obesity and blood pressure levels, the neointimal area in lepr(s/s) mice was significantly increased compared with lepr(db/db) mice. CONCLUSIONS: The molecular mechanism by which the leptin receptor mediates neointima formation and vascular smooth muscle cell proliferation is largely independent of the STAT3-dependent signaling pathways involved in energy balance.

Animals↗
PubMed1997

Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway.

A mechanism by which members of the ciliary neurotrophic factor (CNTF)-leukemia inhibitory factor cytokine family regulate gliogenesis in the developing mammalian central nervous system was characterized. Activation of the CNTF receptor promoted differentiation of cerebral cortical precursor cells into astrocytes and inhibited differentiation of cortical precursors along a neuronal lineage. Although CNTF stimulated both the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and Ras-mitogen-activated protein kinase signaling pathways in cortical precursor cells, the JAK-STAT signaling pathway selectively enhanced differentiation of these precursors along a glial lineage. These findings suggest that cytokine activation of the JAK-STAT signaling pathway may be a mechanism by which cell fate is controlled during mammalian development.

Animals↗
PubMed2002

Control of cell survival by IGF signaling pathways.

The insulin-like growth factor system efficiently signals to cells to grow, differentiate, and survive. One central player in the prevention of cell death is the IGF-I receptor. Transduction of signals through this receptor leads to multiple series of intracellular phosphorylation events and the activation of several signaling pathways. Mechanisms of IGF system signaling that prevent cell death continue to be identified, suggesting that cells have alternative ways to avert death signals in addition to primary protective pathways. This review describes current knowledge of the mechanisms utilized by the IGF system to promote cell survival.

Animals↗
PubMedDate not supplied

Lyn, one of the Src-family tyrosine kinases expressed in phagocytes, plays an important role in beta2 integrin-signalling pathways in opsonized zymosan-activated macrophage-like U937 cells.

We have investigated the contribution of Hck, Lyn and Fgr, highly expressed Src family tyrosine kinases (SFKs) in signalling pathways in opsonized zymosan (OZ)-activated phagocytes by using short interfering RNAs (siRNAs). Treatment of macrophage-like U937 cells with the siRNAs targeted to these transcripts decreased the protein content of each kinase to less than half that of untreated cells. Among these siRNAs, siRNA targeted to Lyn was the most effective in diminishing two kinds of phagocyte functions, that is oxidative burst and phagocytosis. Phosphorylation of c-Cbl, a multidomain adaptor protein in the beta2 integrin-signalling pathway, was also largely inhibited by treatment with siRNA to Lyn. Thus, the results with siRNAs highly specific for Hck, Lyn and Fgr suggested that, among these three SFKs, Lyn plays the most important role in signalling pathways downstream of beta2 integrins in OZ-stimulated phagocytes.

CD18 Antigens↗
PubMed2006

Nitric oxide/cGMP signaling pathway protects RAW264 cells against nitric oxide-induced apoptosis by inhibiting the activation of p38 mitogen-activated protein kinase.

Nitric oxide (NO) induces apoptosis in various cells lines, while activation of the NO/cGMP signaling pathway prevents apoptosis induced by diverse stimuli, including NO. Here, we report the cytoprotective mechanisms of the NO/cGMP signaling pathway against NO-induced apoptosis in a mouse macrophage-like cell line, RAW264. Treatment with sodium nitroprusside (SNP), an NO donor, at a high-toxic concentration (4 mM) stimulated the N-terminal conformational change of Bax and its translocation to mitochondria followed by cytochrome c release and nuclear fragmentation in RAW264 cells. These changes of Bax were attenuated by pretreatment with SNP at a low-nontoxic concentration (100 microM) or dibutyryl cGMP (DBcGMP), a cell-permeable cGMP analogue. SB203580, a p38 mitogen-activated protein kinase (MAP kinase) inhibitor, blocked the effects of 4 mM SNP on Bax translocation and cell viability. Treatment with 4 mM SNP activated p38 MAP kinase and this effect was prevented by pretreatment with 100 microM SNP or DBcGMP. These findings suggest that the NO/cGMP signaling pathway inhibits NO-induced apoptosis of macrophages by suppressing the p38 MAP kinase activation, which results in N-terminal conformational change of Bax and its translocation to mitochondria.

Animals↗
PubMed2004

Convergence of interferon-gamma and progesterone signaling pathways in human endometrium: role of PIASy (protein inhibitor of activated signal transducer and activator of transcription-y).

All cardinal events during the reproductive cycle, including ovulation, implantation, and menstruation, are characterized by a profound tissue remodeling and an associated local inflammatory response. The ovarian hormone progesterone is a key modulator of inflammatory signals in reproductive tissues, but the underlying mechanisms are not well understood. In this study, we report that differentiating human endometrial stromal cells (ESCs) acquire resistance to interferon-gamma (IFNgamma)-dependent signal transducers and activators of transcription (STAT) 1 signaling, although phosphorylation, nuclear translocation, and binding of STAT1 to DNA, are unaffected. These observations prompted an investigation into the role of nuclear repressors of STAT1 signaling. We demonstrate that protein inhibitor of activated STAT-y is complexed to the progesterone receptor (PR) in human ESCs and that its ability to repress STAT1 signaling is dependent upon activation of PR in response to hormone binding. Conversely, IFNgamma and protein inhibitor of activated STAT-y synergistically inhibited PR-dependent transcription, demonstrating that the progesterone and IFNgamma signaling pathways engage in reciprocal transcriptional antagonism in human endometrium.

Cell Differentiation↗
PubMed1998

The cellular response to oxidative stress: influences of mitogen-activated protein kinase signalling pathways on cell survival.

The mammalian response to stress is complex, often involving multiple signalling pathways that act in concert to influence cell fate. To examine potential interactions between the signalling cascades, we have focused on the effects of a model oxidant stress in a single cell type through an examination of the relative influences of mitogen-activated protein kinases (MAPKs) as well as two proposed apoptosis regulators, nuclear factor kappaB (NF-kappaB) and Bcl-2, in determining cell survival. Treatment of HeLa cells with H2O2 resulted in a time- and dose-dependent induction of apoptosis accompanied by sustained activation of all three MAPK subfamilies: extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38. This H2O2-induced apoptosis was markedly enhanced when ERK2 activation was selectively inhibited by PD098059. Apoptosis decreased when JNK/SAPK activation was inhibited by expression of a dominant negative mutant form of SAPK/ERK kinase 1. Inhibition of the p38 kinase activity with p38-specific inhibitors SB202190 and SB203580 had no effect on cell survival. Because NF-kappaB activation by H2O2 is potentially related to both the ERK and JNK/SAPK signalling pathways, we examined the effects of inhibiting the activation of NF-kappaB; this interference had no effect on the cellular response to H2O2. Overexpression of the anti-apoptotic protein Bcl-2 significantly decreased the apoptosis seen after treatment with H2O2 without altering ERK or JNK/SAPK activities. Our results suggest that ERK and JNK/SAPK act in opposition to influence cell survival in response to oxidative stress, whereas neither p38 nor NF-kappaB affects the outcome. Bcl-2 acts independently and downstream of ERK and JNK/SAPK to enhance the survival of H2O2-treated cells.

3T3 Cells↗
PubMed2005

Changes in the Wnt signalling pathway in gastrointestinal cancers and their prognostic significance.

Many steps in the Wnt signalling pathway may be altered during the process of carcinogenesis. This Review focuses on the changes observed in gastrointestinal cancers. A literature search was undertaken and the currently available data summarised. Understanding the alterations to this signalling pathway may help to reveal future targets for therapeutic agents. In addition, since in some tumours, levels of components of the Wnt pathway have been found to correlate with clinical stage, their potential use as prognostic indicators is highlighted.

Axin Protein↗
PubMed2004

Hypoxia-responsive growth factors upregulate periostin and osteopontin expression via distinct signaling pathways in rat pulmonary arterial smooth muscle cells.

This study tested the hypothesis that expression of the novel adhesion molecule periostin (PN) and osteopontin (OPN) is increased in lung and in isolated pulmonary arterial smooth muscle cells (PASMCs) in response to the stress of hypoxia and explored the signaling pathways involved. Adult male rats were exposed to 10% O2 for 2 wk, and growth-arrested rat PASMCs were incubated under 1% O2 for 24 h. Hypoxia increased PN and OPN mRNA expression in rat lung. In PASMCs, hypoxia increased PN but not OPN expression. The hypoxia-responsive growth factors fibroblast growth factor-1 (FGF-1) and angiotensin II (ANG II) caused dose- and time-dependent increases in PN and OPN expression in PASMCs. FGF-1-induced PN expression was blocked by the FGF-1 receptor antagonist PD-166866 and by inhibitors of phosphatidylinositol 3-kinase (PI3K) (LY-294002, wortmannin), p70S6K (rapamycin), MEK1/2 (U-0126, PD-98059), and p38MAPK (SB-203580) but not of JNK (SP-600125). ANG II-induced PN expression was blocked by the AT(1)-receptor antagonist losartan and by inhibitors of PI3K and MEK1/2. In contrast, FGF-1-induced OPN expression was blocked by inhibitors of JNK or MEK1/2 but not of PI3K, p70S6K, or p38MAPK. Activation of p70S6K and p38MAPK by anisomycin robustly stimulated PN but not OPN expression. This study is the first to demonstrate that growth factor-induced expression of PN in PASMCs is mediated through PI3K/p70S6K, Ras/MEK1/2, and Ras/p38MAPK signaling pathways, whereas the expression of OPN is mediated through Ras/MEK1/2 and Ras/JNK signaling pathways. These differences in signaling suggest that PN and OPN may play different roles in pulmonary vascular remodeling under pathophysiological conditions.

Animals↗