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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic inflammatory states are associated with increased bone loss. This increase is often linked to an elevation in receptor activator of nuclear factor-kappaB ligand (RANKL), a TNFalpha-like factor essential to osteoclast formation. In this study, we document the ability of IL-6 in combination with IL-6 soluble receptor (IL-6/IL-6sR) and oncostatin M to induce Rankl expression in stromal cells via signal transducer and activator of transcription 3 (STAT3). We used chromatin immunoprecipitation-tiled DNA microarray analysis to determine sites of action of STAT3 at the Rankl locus and to assess the consequences of binding on histone H4 acetylation and RNA polymerase II recruitment. Both IL-6/IL-6 soluble receptor and oncostatin M stimulated STAT3 binding upstream of the Rankl transcriptional start site. Although previously identified enhancers bound STAT3, a more distal enhancer termed mRLD6 was a particular focus of STAT3 binding. When fused to a heterologous promoter, this enhancer was highly active, containing two functionally active STAT response elements. Importantly, small interfering RNA knockdown of Stat3 mRNA and protein, but not that of Stat1 or Stat5a, was effective in limiting Rankl mRNA up-regulation. Interestingly, although RNA polymerase II and histone H4 acetylation marked many of the enhancers under basal conditions, the levels of both were strongly increased after cytokine treatment, particularly at mRLD6. Finally, mRLD6 was also a target for forskolin-induced cellular response element-binding protein (CREB) recruitment, which potentiated cytokine activity. Our studies provide new insight into mechanisms by which glycoprotein 130 activating cytokines induce RANKL expression.
Mol Endocrinol 2009 Dec
PMID:A novel distal enhancer mediates cytokine induction of mouse RANKl gene expression. 1988 Jun 55

Abnormal vascular smooth muscle cell (VSMC) proliferation contributes to the pathogenesis of restenosis. Thus, drugs interfering with cell cycle progression in VSMC are promising candidates for an antirestenotic therapy. In this study, we pharmacologically characterize N-5-(2-aminocyclohexyl)-N-7-benzyl-3-isopropyl-1(2)H-pyrazolo[4,3-d]pyrimidine-5,7-di-amine (LGR1406), a novel derivative of the cyclin-dependent kinase (CDK) inhibitor roscovitine (ROSC), in PDGF-BB-activated VSMC. Cell proliferation was quantified measuring DNA synthesis via 5-bromo-2'-deoxyuridine incorporation. Analysis of cell cycle distribution was done by flow cytometry using propidium iodide-stained nuclei. Key regulators of the cell cycle and relevant signaling pathways were dissected by Western blot analyses. In addition, in vitro kinase assays and in silico studies regarding the pharmacokinetic profile of both compounds were performed. LGR1406 shows a stronger (IC(50) = 3.0 muM) antiproliferative activity than ROSC (IC(50) = 16.9 muM), halting VSMCs in G(0)/G(1) phase of the cell cycle, whereas ROSC does not arrest but rather delays cell cycle progression. Neither of the compounds interferes with early PDGF-BB-induced signaling pathways (p38, extracellular signal-regulated kinase 1/2, c-Jun NH(2)-terminal kinase, Akt, signal transducer and activator of transcription 3), and both inhibit CDKs, with LGR1406 exerting a slightly higher potency against CDK1/2 and 4 than ROSC. Expression of cyclins A and E as well as hyperphosphorylation of the pocket proteins retinoblastoma protein and p107 are negatively affected by both compounds, although to a different extent. In silico calculations predicted a much higher metabolic stability for LGR1406 compared with ROSC. Altogether, ROSC derivatives, such as LGR1406 seem to be promising compounds for further development in antirestenotic therapy.
Mol Pharmacol 2010 Feb
PMID:A novel roscovitine derivative potently induces G1-phase arrest in platelet-derived growth factor-BB-activated vascular smooth muscle cells. 1990 26

Psoriasis is a chronic inflammatory skin disease characterised by elevated red scaly plaques on specific body sites. Histologically, the plaques are defined by epidermal hyperplasia, epidermal and dermal infiltration by leukocytes, and changes in the dermal microvasculature. Differentiation and activation are disturbed in lesional psoriatic keratinocytes, and the pool of proliferating keratinocytes is increased, which is accompanied by enhanced production of proinflammatory cytokines, adhesion molecules and antimicrobial peptides. These changes in psoriatic keratinocytes are caused by altered expression of genes associated with epidermal differentiation, and by activation of signalling pathways involving signal transducer and activator of transcription 3 (STAT3), type I interferon (IFN) and mitogen-activated protein kinase (MAPK). The number of T cells, and myeloid and plasmacytoid dendritic cells (DCs) is markedly increased in psoriatic lesions. Myeloid DCs produce interleukin (IL)-23, tumour necrosis factor (TNF)-alpha and inducible nitric oxide synthase (iNOS), which are crucial cytokines in the pathogenesis of psoriasis. IL-23 stimulates the secretion of IL-22 by T helper 17 cells, and IL-22 induces epidermal hyperplasia. The crosstalk between keratinocytes and leukocytes via their proinflammatory cytokines creates the vicious circle of chronic skin inflammation seen in psoriasis. This suggests that optimal treatment of psoriasis needs to target pathogenic pathways in both leukocytes and keratinocytes.
Expert Rev Mol Med 2009 Dec 14
PMID:Molecular pathophysiology of psoriasis and molecular targets of antipsoriatic therapy. 2000 7

The oncogenic transcription factor Stat3 is constitutively active in a high percentage of human tumors including mammary adenocarcinomas and is reported to participate in the ErbB-2 oncogene signaling. In order to assess the role of signal transducer and activator of transcription 3 (Stat3) in mammary tumorigenesis downstream of ErbB-2, we generated mice expressing the activated rat ErbB-2 (neu) but lacking Stat3 in the mammary epithelium. Stat3 is apparently not required for neu-driven mammary tumorigenesis as tumors developed similarly in both Stat3-sufficient and Stat3-deficient glands. However, short hairpin RNA (shRNA)-mediated Stat3 silencing in a neu-overexpressing tumor-derived cell line completely abolished both neu-driven anchorage-independent growth and lung metastasis. Our data suggest that Stat3 might be a useful therapeutic target in breast tumors showing amplification and/or overexpression of the ErbB-2 oncogene, which normally display aggressive, metastatic behavior.
Mol Carcinog 2010 Feb
PMID:Stat3 is required for anchorage-independent growth and metastasis but not for mammary tumor development downstream of the ErbB-2 oncogene. 2002 36

Medulloblastomas are the most frequent malignant brain tumors in children. Sunitinib is an oral multitargeted tyrosine kinase inhibitor used in clinical trials as an antiangiogenic agent for cancer therapy. In this report, we show that sunitinib induced apoptosis and inhibited cell proliferation of both a short-term primary culture (VC312) and an established cell line (Daoy) of human medulloblastomas. Sunitinib treatment resulted in the activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase and upregulation of proapoptotic genes, Bak and Bim, and inhibited the expression of survivin, an antiapoptotic protein. Sunitinib treatment also downregulated cyclin E, cyclin D2, and cyclin D3 and upregulated p21Cip1, all of which are involved in regulating cell cycle. In addition, it inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) and AKT (protein kinase B) in the tumor cells. Dephosphorylation of STAT3 (Tyr(705)) induced by sunitinib was helped by a reduction in activities of Janus-activated kinase 2 and Src. Additionally, sodium vanadate, an inhibitor of protein tyrosine phosphatases, partially blocked the inhibition of phosphorylated STAT3 by sunitinib. Loss of phosphorylated AKT after sunitinib treatment was accompanied by decreased phosphorylation of downstream proteins glycogen synthase kinase-3beta and mammalian target of rapamycin. Expression of a constitutively activated STAT3 mutant or myristoylated AKT partially blocked the effects of sunitinib in these tumor cells. Sunitinib also inhibited the migration of medulloblastoma tumor cells in vitro. These findings suggest the potential use of sunitinib for the treatment of pediatric medulloblastomas.
Mol Cancer Res 2010 Jan
PMID:Sunitinib induces apoptosis and growth arrest of medulloblastoma tumor cells by inhibiting STAT3 and AKT signaling pathways. 2005 26

Gain-of-function mutations of the receptor tyrosine kinase KIT play a critical role in the pathogenesis of systemic mastocytosis (SM) and gastrointestinal stromal tumors. The various juxtamembrane type of KIT mutations, including V560G, are found in 60% to 70% of patients with gastrointestinal stromal tumors; loop mutant D816V, which exists in approximately 80% of SM patients, is completely resistant to imatinib. In the present study, we hypothesized that homoharringtonine (HHT), a protein synthesis inhibitor, would decrease the level of KIT protein by inhibiting translation, resulting in a decreased level of phospho-KIT and abrogating its constitutive downstream signaling. Imatinib-sensitive HMC-1.1 cells harboring the mutation V560G in the juxtamembrane domain of KIT, imatinib-resistant HMC-1.2 cells harboring both V560G and D816V mutations, and murine P815 cells were treated with HHT and analyzed in terms of growth, apoptosis, and signal transduction. The in vivo antitumor activity was evaluated by using the murine mast cell leukemia model. Our results indicated that HHT effectively inhibited the growth and induced apoptosis in cells bearing both V560G and D816V or D814Y KIT. Additionally, HHT inhibited the KIT-dependent phosphorylation of downstream signaling molecules Akt, signal transducer and activator of transcription 3 and 5, and extracellular signal-regulated kinase 1/2. Furthermore, HHT significantly prolonged the survival duration of mice with aggressive SM or mast cell leukemia by inhibiting the expansion and infiltration of imatinib-resistant mast tumor cells harboring imatinib-resistant D814Y KIT. Collectively, we show that HHT circumvents D816V KIT-elicited imatinib resistance. Our findings warrant a clinical trial of HHT in patients with SM harboring D816V or D814Y KIT.
Mol Cancer Ther 2010 Jan
PMID:The antitumor activity of homoharringtonine against human mast cells harboring the KIT D816V mutation. 2005 66

Glioblastoma multiforme (GBM) is a lethal cancer that responds poorly to radiotherapy and chemotherapy. Glioma cancer-initiating cells have been shown to recapitulate the characteristic features of GBM and mediate chemotherapy and radiation resistance. However, it is unknown whether the cancer-initiating cells contribute to the profound immune suppression in GBM patients. Recent studies have found that the activated form of signal transducer and activator of transcription 3 (STAT3) is a key mediator in GBM immunosuppression. We isolated and generated CD133+ cancer-initiating single colonies from GBM patients and investigated their immune-suppressive properties. We found that the cancer-initiating cells inhibited T-cell proliferation and activation, induced regulatory T cells, and triggered T-cell apoptosis. The STAT3 pathway is constitutively active in these clones and the immunosuppressive properties were markedly diminished when the STAT3 pathway was blocked in the cancer-initiating cells. These findings indicate that cancer-initiating cells contribute to the immune evasion of GBM and that blockade of the STAT3 pathway has therapeutic potential.
Mol Cancer Ther 2010 Jan
PMID:Glioblastoma cancer-initiating cells inhibit T-cell proliferation and effector responses by the signal transducers and activators of transcription 3 pathway. 2005 72

Emerging evidence indicates a novel mode of epidermal growth factor receptor (EGFR) signaling, notably, one involves EGFR nuclear translocalization and subsequent gene activation. To date, however, the significance of the nuclear EGFR pathway in glioblastoma (GBM) is unknown. Here, we report that EGFR and its constitutively activated variant EGFRvIII undergo nuclear translocalization in GBM cells, in which the former event requires EGF stimulation and the latter is constitutive. To gain insights into the effect of nuclear EGFR on gene expression in GBM, we created isogenic GBM cell lines, namely, U87MG-vector, U87MG-EGFR, and U87MG-EGFRdNLS that, respectively, express the control vector, EGFR, and nuclear entry-defective EGFR with a deletion of the nuclear localization signal (NLS). Microarray analysis shows that 19 genes, including cyclooxygenase-2 (COX-2), to be activated in U87MG-EGFR cells but not in U87MG-EGFRdNLS and U87MG-vector cells. Subsequent validation studies indicate that COX-2 gene is expressed at higher levels in cells with EGFR and EGFRvIII than those with EGFRdNLS and EGFRvIIIdNLS. Nuclear EGFR and its transcriptional cofactor signal transducer and activator of transcription 3 (STAT3) associate with the COX-2 promoter. Increased expression of EGFR/EGFRvIII and activated STAT3 leads to the synergistic activation of the COX-2 promoter. Promoter mutational analysis identified a proximal STAT3-binding site that is required for EGFR/EGFRvIII-STAT3-mediated COX-2 gene activation. In GBM tumors, an association exists between levels of COX-2, EGFR/EGFRvIII, and activated STAT3. Together, these findings indicate the existence of the nuclear EGFR/EGFRvIII signaling pathway in GBM and its functional interaction with STAT3 to activate COX-2 gene expression, thus linking EGFR-STAT3 and EGFRvIII-STAT3 signaling axes to proinflammatory COX-2 mediated pathway.
Mol Cancer Res 2010 Feb
PMID:Cyclooxygenase-2 is a novel transcriptional target of the nuclear EGFR-STAT3 and EGFRvIII-STAT3 signaling axes. 2014 33

The hyper-IgE syndrome (HIES) is a rare primary immunodeficiency characterized by a highly elevated serum IgE, recurrent staphylococcal skin abscesses and cyst-forming pneumonia. Non-immunological abnormalities, including a distinctive facial appearance, hyperextensive joints, scoliosis, fracture following minor trauma, and the retention of primary teeth are also observed in many patients. Recently, it was shown that heterozygous mutations in signal transducer and activator of transcription 3 (STAT3), can cause autosomal-dominant HIES. Here we identify and characterize a novel mutation in the DNA-binding domain of STAT3 in a patient with hyper-IgE syndrome. Sequence analysis revealed a de novo heterozygous transition of a G-to-A, causing a substitution of a glycine residue for an aspartic acid in the translated sequence (G342D). The patient has normal levels of STAT3, which is able to translocate to the nucleus upon IL-6 stimulation. However, enzyme-linked DNA-protein interaction analysis showed that the G342D mutation affects the binding ability of STAT3 to target DNA sequences. In addition, as shown by qRT-PCR, the mutation abrogates the STAT3-dependent transcription of the retinoid-related orphan receptor gammat (ROR gammat) gene, an indispensable transcription factor for the commitment of naive CD4+ T cells to the Th17 lineage. These data suggest that the novel G342D mutation affects the binding of STAT3 on DNA and the STAT3-dependent expression of ROR gammat mRNA, leading to the HIES phenotype.
Mol Immunol 2010 Apr
PMID:A novel mutation in the signal transducer and activator of transcription 3 (STAT3) gene, in hyper-IgE syndrome. 2014 60

Effective stroke therapies require recanalization of occluded cerebral blood vessels. However, reperfusion can cause neurovascular injury, leading to cerebral edema, brain hemorrhage, and neuronal death by apoptosis/necrosis. These complications, which result from excess production of reactive oxygen species in mitochondria, significantly limit the benefits of stroke therapies. We have developed a focal stroke model using mice deficient in mitochondrial manganese-superoxide dismutase (SOD2-/+) to investigate neurovascular endothelial damage that occurs during reperfusion. Following focal stroke and reperfusion, SOD2-/+ mice had delayed blood-brain barrier breakdown, associated with activation of matrix metalloproteinase and high brain hemorrhage rates, whereas a decrease in apoptosis and hemorrhage was observed in SOD2 overexpressors. Thus, induction and activation of SOD2 is a novel strategy for neurovascular protection after ischemia/reperfusion. Our recent study identified the signal transducer and activator of transcription 3 (STAT3) as a transcription factor of the mouse SOD2 gene. During reperfusion, activation of STAT3 and its recruitment into the SOD2 gene were blocked, resulting in increased oxidative stress and neuronal apoptosis. In contrast, pharmacological activation of STAT3 induced SOD2 expression, which limits ischemic neuronal death. Our studies point to antioxidant-based neurovascular protective strategies as potential treatments to expand the therapeutic window of currently approved therapies.
Mol Neurobiol 2010 Jun
PMID:Reperfusion and neurovascular dysfunction in stroke: from basic mechanisms to potential strategies for neuroprotection. 2015 89


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