Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The growth of melanocytes and many early stage melanoma cells can be inhibited by cytokines, whereas late stage melanoma cells have often been reported to be "multi-cytokine-resistant." Here, we analyzed the melanoma cell line 1286, resistant towards the growth-inhibitory effects of interleukin 6 (IL-6), and oncostatin M (OSM), to better understand the mechanisms underlying cytokine resistance. Although the relevant receptors gp130 and OSMR are expressed at the cell surface of these cells, cytokine stimulation hardly led to the activation of Janus kinase 1 and signal transducer and activator of transcription (STAT)3 and STAT1. We found a high-level constitutive expression of suppressors of cytokine signaling 3 (SOCS3) that did not further increase after cytokine treatment. Importantly, upon suppression of SOCS3 by short interfering RNA, cells became susceptible towards OSM and IL-6: they showed an enhanced STAT3 phosphorylation and a dramatically increased STAT1 phosphorylation. Moreover, suppression of SOCS3 rendered 1286 cells sensitive to the antiproliferative action of IL-6 and OSM, but not of IFN-alpha. Interestingly, SOCS3-short interfering RNA treatment also increased the growth-inhibitory effect in cytokine-sensitive WM239 cells expressing SOCS3 in an inducible way. Thus, SOCS3 expression confers a growth advantage to these cell lines. Constitutive SOCS3 mRNA expression, although at lower levels than in 1286 cells, was found in nine additional human melanoma cell lines and in normal human melanocytes, although at the protein level, SOCS3 expression was marginal at best. However, in situ analysis of human melanoma specimens revealed SOCS3 immunoreactivity in 3 out of 10 samples, suggesting that in vivo SOCS3 may possibly play a role in IL-6 resistance in at least a fraction of tumors.
Mol Cancer Res 2007 Mar
PMID:Constitutive suppressor of cytokine signaling 3 expression confers a growth advantage to a human melanoma cell line. 1737 32

Double-stranded RNA (dsRNA) and its mimic, polyinosinic acid:polycytidylic acid [poly(I):poly(C)], are recognized by toll-like receptor 3 (TLR3) that induces the production of IFN-beta in many cell types. In the present study, we investigated the effects of poly(I):poly(C) on mouse osteoblastic MC3T3-E1 (E1) cells. Poly(I):poly(C) markedly increased IFN-beta mRNA level in a dose-dependent manner. The increase in the IFN-beta mRNA level was apparent as early as 1 h after adding poly(I):poly(C) to the culture and peaked at 12 h. Stimulation with poly(I):poly(C) enhanced the expression of CXCL10 mRNA and TLR3 in E1 cells. Moreover, poly(I):poly(C) induced tyrosine phosphorylation of the transcription factor STAT1 in E1 cells. An anti-IFN-beta neutralizing antibody partially inhibited poly(I):poly(C)-induced CXCL10 mRNA, TLR3 mRNA and STAT1 phosphorylation. These results indicate that osteoblasts secrete IFN-beta in response to viral infection and that endogenous IFN-beta induces both CXCL10 and TLR3 production via an IFN-alpha/beta receptor-STAT1 pathway. It is suggested that osteoblasts are involved in host defense as well as bone metabolism.
Int J Mol Med 2007 May
PMID:Toll-like receptor 3 ligand-induced antiviral response in mouse osteoblastic cells. 1739 82

Type I interferons (IFN-alpha/beta) induce apoptosis in certain tumor cell lines but not others. Here we describe a mutation in STAT2 that confers an apoptotic effect in tumor cells in response to type I IFNs. This mutation was introduced in a conserved motif, PYTK, located in the STAT SH2 domain, which is shared by STAT1, STAT2, and STAT3. To test whether the tyrosine in this motif might be phosphorylated and affect signaling, Y631 of STAT2 was mutated to phenylalanine (Y631F). Although it was determined that Y631 was not phosphorylated, the Y631F mutation conferred sustained signaling and induction of IFN-stimulated genes. This prolonged IFN response was associated with sustained tyrosine phosphorylation of STAT1 and STAT2 and their mutual association as heterodimers, which resulted from resistance to dephosphorylation by the nuclear tyrosine phosphatase TcPTP. Finally, cells bearing the Y631F mutation in STAT2 underwent apoptosis after IFN-alpha stimulation compared with wild-type STAT2. Therefore, this mutation reveals that a prolonged response to IFN-alpha could account for one difference between tumor cell lines that undergo IFN-alpha-induced apoptosis compared with those that display an antiproliferative response but do not die.
Mol Biol Cell 2007 Jul
PMID:A Mutation in the SH2 domain of STAT2 prolongs tyrosine phosphorylation of STAT1 and promotes type I IFN-induced apoptosis. 1744 90

The prime anti-viral cytokine interferon-alpha (IFN-alpha) has been implicated in several central nervous system (CNS) disorders in addition to its beneficial effects. Systemic IFN-alpha treatment causes severe neuropsychiatric complications in humans, including depression, anxiety and cognitive impairments. While numerous neuromodulatory effects by IFN-alpha have been described, it remains unresolved whether or not systemic IFN-alpha acts directly on the brain to execute its CNS actions. In the present study, we have analyzed the genes directly regulated in post-IFN-alpha receptor signaling and found that intraperitoneal administration of mouse IFN-alpha, but not human IFN-alpha, activated expression of several prototypic IFN-stimulated genes (ISGs), in particular signal transducers and activators of transcription (STAT1), IFN-induced 15 kDa protein (ISG15), ubiquitin-specific proteinase 18 (USP18) and guanylate-binding protein 3 (GBP3) in the brain. A similar temporal profile for the regulated expression of these IFN-alpha-activated ISG genes was observed in the brain compared with the peripheral organs. Dual labeling in situ hybridization combined with immunocytochemical staining demonstrated a wide distribution of the key IFN-regulated gene STAT1 transcripts in the different parenchyma cells of the brain, particularly neurons. The overall response to IFN-alpha challenge was abolished in STAT1 knockout mice. Together, our results indicate a direct, STAT1-dependent action of systemic IFN-alpha in the CNS, which may provide the basis for a mechanism in humans for neurological/neuropsychiatric illnesses associated with IFN-alpha therapy.
Mol Psychiatry 2008 Mar
PMID:Systemic interferon-alpha regulates interferon-stimulated genes in the central nervous system. 1748 6

We recently reported that nitric oxide (NO) modulates expression of multiple genes associated with apoptotic pathways, including expression of caspase-8. The objective of the present study is to determine whether the NO-induced expression of the caspase-8 gene is regulated via signal transducers and activators of transcription-1 (STAT-1) signaling. The confluent monolayers of pulmonary artery endothelial cells (PAEC) were incubated with or without (control) 1 mM NOC-18, a NO donor, at 37 degrees C for 0-24 h. In some experiments PAEC were pretreated with a Janus kinase (JAK-2) inhibitor, AG490 (20 microM). Exposure of PAEC to NO-increased relative levels of caspase-8 mRNA as determined using quantitative real time PCR. Relative levels of phosphorylated STAT-1 at Serine (Ser)-727, but not total STAT-1 expression in NO-exposed cells, were upregulated significantly compared to control cells. AG490 attenuated NO-induced phosphorylation of STAT-1 at Ser 727 and expression of caspase-8 mRNA, suggesting JAK2 plays a role in the induction of caspase-8 mRNA. The promoter of caspase-8 has four gamma-activated sequence (GAS) and two interferon-stimulated response element (ISRE) transcription factor-binding sites. NO enhanced the STAT-1 binding activity to GAS/ISRE. Suppression of STAT-1 expression attenuated NO-induced elevation of caspase-8 mRNA. These studies demonstrate that a NO-dependent increase in caspase-8 mRNA levels is associated with phosphorylation of STAT-1 at Ser-727 and STAT1 binding to the caspase-8 promoter in cultured PAEC.
Mol Cell Biochem 2007 Nov
PMID:Nitric oxide upregulation of caspase-8 mRNA expression in lung endothelial cells: role of JAK2/STAT-1 signaling. 1756 48

We previously showed that the MUC5B gene expression was elevated by phorbol 12-myristate 13-acetate (PMA) through an epidermal growth factor receptor-independent Ras/MEKK1/JNK and P38 signaling-based transcriptional mechanism. In the current study, we elucidated the molecular basis of this transcriptional regulation using promoter-reporter gene expression and chromatin immunoprecipitation (ChIP) assays with primary human bronchial epithelial cells that are cultured at the air-liquid interface. We have observed that PMA-induced MUC5B promoter activity is blocked by the Sp1-binding inhibitor, mithramycin A, in a dose-dependent manner. Deletion analysis with the MUC5B promoter construct demonstrated that both basal and PMA-induced promoter-reporter activities reside within the -222/-78 bp region relative to the transcriptional start site. NoShift transcriptional factor assays demonstrated that PMA stimulated Sp1 binding, but not STAT1 and c-Myc binding. Immunoprecipitation studies also verified the enhanced phosphorylation of Sp1 after PMA treatment. Site-directed mutagenesis and transfection studies demonstrated the involvement of Sp1-1 (-122/-114) and the Sp1-2 (-197/-186) cis elements in the basal and PMA-induced MUC5B promoter activity. The ChIP assay with anti-RNA polymerase II reconfirmed the PMA-induced MUC5B promoter activity by showing enhanced RNA polymerase II-DNA complex containing putative MUC5B Sp1-1, Sp1-2, or Sp1-3 sites. However, the ChIP assay using anti-Sp1 antibody demonstrated that the PMA-stimulated binding is only at Sp1-2. These results suggested an Sp1-based transcriptional mechanism with Sp1-1 as the regulator of basal MUC5B promoter activity and Sp1-2 as the regulator of PMA-induced MUC5B gene expression in the human airway epithelial cells.
Am J Respir Cell Mol Biol 2007 Nov
PMID:PMA stimulates MUC5B gene expression through an Sp1-based mechanism in airway epithelial cells. 1760 Mar 9

Recent studies have suggested the importance of interleukin (IL)-6 signaling in the development of colon cancer. Expression of IL-6 and the IL-6 receptor have been found to be elevated in colorectal carcinoma tissue, and IL-6 has been found to be critical for tumor formation in mouse models of colon cancer. IL-6 mediated activation of the transcription factor STAT1 has been shown to be important in protection of colorectal carcinoma cells from apoptotic signals. To test the hypothesis that the IL-6-STAT1 axis plays a role in early stages of colon cancer development, we examined the role of this pathway in the mouse multiple intestinal neoplasia (Min) model of intestinal tumorigenesis. Due to low fecundity, we were unable to generate Min mice lacking expression of IL-6. We then focused on the role of STAT1 in intestinal polyp formation in these animals. Min mice lacking STAT1 or heterozygous for STAT1 developed polyps in similar numbers as those expressing STAT1. Furthermore, the anatomic distribution and histological characteristics of these polyps did not vary among these populations. These results indicate that STAT1 does not play a role in the pathogenesis of the Min model for colon cancer. However, they do not rule out the possibility that STAT1 plays a role in other stages of colon cancer development.
Mol Carcinog 2008 Feb
PMID:STAT1 expression is not required for polyp formation in Min mice. 1768 66

A recent study in the North American White population has documented the association of a common STAT4 haplotype (tagged by rs7574865) with risk for rheumatoid arthritis (RA) and systemic lupus erythematosus. To replicate this finding in the Korean population, we performed a case-control association study. We genotyped 67 single nucleotide polymorphisms (SNPs) within the STAT1 and STAT4 regions in 1123 Korean patients with RA and 1008 ethnicity-matched controls. The most significant four risk SNPs (rs11889341, rs7574865, rs8179673, and rs10181656 located within the third intron of STAT4) among 67 SNPs are identical with those in the North American study. All four SNPs have modest risk for RA susceptibility (odds ratio 1.21-1.27). A common haplotype defined by these markers (TTCG) carries significant risk for RA in Koreans [34 percent versus 28 percent, P=0.0027, OR (95 percent CI)=1.33 (1.10-1.60)]. By logistic regression analysis, this haplotype is an independent risk factor in addition to the classical shared epitope alleles at the HLA-DRB1 locus. There were no significant associations with age of disease onset, radiographic progression, or serologic status using either allelic or haplotypic analysis. Unlike several other risk genes for RA such as PTPN22, PADI4, and FCRL3, a haplotype of the STAT4 gene shows consistent association with RA susceptibility across Whites and Asians, suggesting that this risk haplotype predates the divergence of the major racial groups.
Mol Med
PMID:Association of STAT4 with rheumatoid arthritis in the Korean population. 1793 59

Protein kinase R (PKR) is a serine/threonine-specific protein kinase implicated in the control of cell growth, differentiation, interferon-induced antiviral response, and induction of apoptosis. It is activated by various stress signals and growth factors. Activated PKR phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha), thereby inhibiting the initiation of translation. PKR also mediates the activation of several transcription factors (STAT1, p53, and NFkappaB) regulating both pro- and antiapoptotic mechanisms. In the present work, we studied the signaling pathways leading to PKR activation and apoptosis in PC12 rat pheochromocytoma cells, a model system of neuronal differentiation and cell death. We found that administration of various apoptosis inducing agents and conditions (serum starvation, anisomycin, LY294002, etoposide, and cisplatin) led to the proteolytic cleavage of PKR in PC12 cells. This cleavage was in strong correlation with the time kinetics of DNA fragmentation and morphological alterations characteristic of apoptosis. PKR was activated by the proteolytic cleavage: increased phosphorylation of eIF2alpha was found to run parallel with PKR cleavage. The activation of caspase-3 and caspase-9 was stimulated by all apoptosis inducing agents used in this study. The activation of caspase-3 preceded the cleavage of PKR after serum withdrawal, anisomycin and etoposide treatment, while coincided with it in cells treated with LY294002 or cisplatin. These observations suggest that early activation of caspase-3 is upstream of PKR proteolysis and that proteolytic activation of PKR may play a general role in the apoptosis of PC12 cells induced by various forms of cellular stress.
Cell Mol Neurobiol 2008 May
PMID:Involvement of proteolytic activation of protein kinase R in the apoptosis of PC12 pheochromocytoma cells. 1808 Aug 32

Lymphangioleiomyomatosis (LAM), a rare pulmonary disorder, manifests as an abnormal neoplastic growth of smooth muscle-like cells within the lungs. Mutational inactivation of tumor suppressor tuberous sclerosis complex 2 (TSC2) in LAM constitutively activates the mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (S6K1) signaling pathway and promotes neoplastic growth of LAM cells. In many cell types, type I interferon beta (IFNbeta) inhibits proliferation and induces apoptosis through signal transducers and activators of transcription (STAT)-dependent and STAT-independent signaling pathways, one of which is the mTOR/S6K1 signaling pathway. Our study shows that IFNbeta is expressed in LAM tissues and LAM-derived cell cultures; however, IFNbeta attenuates LAM-derived cell proliferation only at high concentrations, 100 and 1000 U/ml (IC(50) value for IFNbeta is 20 U/ml compared with 1 U/ml for normal human mesenchymal cells, human bronchus fibroblasts and human airway smooth muscle cells). Likewise, IFNbeta only attenuates proliferation of smooth muscle TSC2-null ELT3 cells. Analysis of IFNbeta signaling in LAM cells showed expression of IFNbeta receptor alpha (IFNbetaRalpha) and IFNbetaRbeta, activation and nuclear translocation of STAT1, and phosphorylation of STAT3 and p38 mitogen-activated protein kinase (MAPK), but IFNbeta had little effect on S6K1 activity. However, the re-expression of TSC2 or inhibition of mTOR/S6K1 with rapamycin (sirolimus) augmented antiproliferative effects of IFNbeta in LAM and TSC2-null ELT3 cells. Our study demonstrates that IFNbeta-dependent activation of STATs and p38 MAPK is not sufficient to fully inhibit proliferation of cells with TSC2 dysfunction and that TSC2-dependent inhibition of mTOR/S6K1 cooperates with IFNbeta in inhibiting human LAM and TSC2-null ELT3 cell proliferation.
Mol Pharmacol 2008 Mar
PMID:Interferon beta augments tuberous sclerosis complex 2 (TSC2)-dependent inhibition of TSC2-null ELT3 and human lymphangioleiomyomatosis-derived cell proliferation. 1809 73


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