Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05109 (S100A8)
 1,212 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Doxorubicin is a DNA-damaging drug, commonly used for treatment of cancer patients. Doxorubicin causes not only cytotoxic and cytostatic effects, but also inhibits metastasis formation, while TGFbeta1 (Transforming Growth Factor-beta1) is a cytokine that is often up-regulated in human cancers and can promote metastasis formation. We have studied the influence of Doxorubicin on TGFbeta signaling in tumor cells. Here we have demonstrated that Doxorubicin inhibited TGFbeta-signaling in human lung adenocarcinoma A549 cells, namely, it blocked TGFbeta1-induced activation of Smad3-responsive CAGA(12)-Luc reporter, but did not affect c-myc-Luc reporter. That effect was observed as early as after 1-3 h of treating these cells with Doxorubicin, while the other drugs cisplatin or methotrexate did not alter activation of CAGA(12)-Luc reporter under the same conditions. Besides, after 1 h action, Doxorubicin abrogated TGFbeta-induced translocation of Smad3-protein from the cytoplasm to the nucleus. Down-regulation of expression of Smad2, Smad3, and Smad4 proteins, and up-regulation of inhibitory Smad7 protein upon Doxorubicin treatment, were found after 12-24 h of Doxorubicin treatment. Phosphorylation of Smad2/3 proteins was also affected by Doxorubicin. Summarizing, we have found that human tumor cells treatment with Doxorubicin resulted in the inhibition of TGFbeta-signaling at both early (1 h) and later (12 h) stages of the drug action. Such inhibition can be a new potential mechanism for Doxorubicin action towards tumor cells.
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PMID:Doxorubicin inhibits TGF-beta signaling in human lung carcinoma A549 cells. 1860 4

Smad7 is an antagonist of TGF-beta signaling pathway and the mechanism of its inhibitory effect is of great interest. We recently found that Smad7 could function in the nucleus by binding to the DNA elements containing the minimal Smad binding element CAGA box. In this work, we further applied single-molecule force spectroscopy to study the DNA-binding property of Smad7. Smad7 showed similar binding strength to the oligonucleotides corresponding to the CAGA-containing activin responsive element (ARE) and the PAI-1 promoter, as that of Smad4. However, Smad7 also exhibited a binding activity to the mutant ARE with the CAGA sequence substituted, indicating its DNA-binding specificity is different from other Smads. Moreover, we demonstrated that the MH2 domain of Smad7 had a higher binding affinity to the DNA elements than the full-length Smad7, while the N-terminal domain exhibited an inhibitory effect.
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PMID:Study of interaction between Smad7 and DNA by single-molecule force spectroscopy. 1899 14

PAI-1 (plasminogen activator inhibitor-1) is a member of plasminogen cascade with an inhibitory role in plasmin activation. Plasmin is a protease capable of acting on wide range of substrates and, together with metaloproteinases, is a main proteolytic enzyme. Except its role in plasminogen cascade, PAI-1 has an affinity to vitronectin and uPA/uPAR what involves PAI-1 in cell's motility. PAI-1 gene is regulated in response to cytokines, hormones and many growth factors among which TGFbeta is the most important one. The PAI-1 promoter contains SBE, CAGA box, HRE, ERE, NFkB - binding sites, Sp-1, AP-1 and other. Cooperation between transcription factors bound to promoter and cross-talks between kinases and other upstream proteins decide about gene expression. This work describes the present knowledge in this field.
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PMID:[Regulation of PAI-1 expression]. 1951 65

Endoglin (ENG) promotes angiogenesis by enhancing activation of TGF-beta type I receptors ALK-1 and ALK-5. ALK-1 phosphorylates transcription factors SMAD1/5, which bind to BMP-responsive elements (BRE), whereas ALK-5 phosphorylates SMAD3, which binds to CAGA elements. Expression of ENG is increased during myocardial infarction (MI). We investigated which ENG signaling pathway is activated in endothelial cells during hypoxia. Expression of ENG, ALK-1, ALK-5, and phosphorylated SMAD1/3/5 by immunostaining and immunoblotting in a mouse model of myocardial infarction (MI) and in hypoxic human aortic endothelial cells (HAECs) was evaluated. Activation of BRE and CAGA was measured by luciferase assays in cells transfected with plasmids expressing ENG or ALK-1 and the number of cells was quantified. mRNA expression of the target genes of TGF-beta signaling, ID1 and BCL-X, was quantified by real-time RT-PCR. Expression of ENG, ALK-1 and phosphorylated SMAD1/5, but not ALK-5 or phosphorylated SMAD3, was significantly increased in hypoxic endothelial cells in vivo and in vitro. Overexpression of both ENG and ALK-1 significantly increased BRE but not CAGA activity, expression of ID1 and BCL-X and the number of HAECs at hypoxia. ENG/ALK-1 signaling is one of the factors that regulate endothelial cell activity during adaptive cardiac angiogenesis.
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PMID:Endothelial cells are activated during hypoxia via endoglin/ALK-1/SMAD1/5 signaling in vivo and in vitro. 2006 Aug 13

Connective tissue growth factor (CTGF/CCN2) is a matricellular protein induced by transforming growth factor (TGF)-beta and intimately involved with tissue repair and overexpressed in various fibrotic conditions. We previously showed that keratinocytes in vitro downregulate TGF-beta-induced expression of CTGF in fibroblasts by an interleukin (IL)-1 alpha-dependent mechanism. Here, we investigated further the mechanisms of this downregulation by both IL-1alpha and beta. Human dermal fibroblasts and NIH 3T3 cells were treated with IL-1alpha or beta in presence or absence of TGF-beta1. IL-1 suppressed basal and TGF-beta-induced CTGF mRNA and protein expression. IL-1alpha and beta inhibited TGF-beta-stimulated CTGF promoter activity, and the activity of a synthetic minimal promoter containing Smad 3-binding CAGA elements. Furthermore, IL-1alpha and beta inhibited TGF-beta-stimulated Smad 3 phosphorylation, possibly linked to an observed increase in Smad 7 mRNA expression. In addition, RNA interference suggested that TGF-beta activated kinase1 (TAK1) is necessary for IL-1 inhibition of TGF-beta-stimulated CTGF expression. These results add to the understanding of how the expression of CTGF in human dermal fibroblasts is regulated, which in turn may have implications for the pathogenesis of fibrotic conditions involving the skin.
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PMID:Inhibition of connective tissue growth factor/CCN2 expression in human dermal fibroblasts by interleukin-1alpha and beta. 2054 97

Ovarian folliculogenesis is driven by the combined action of endocrine cues and paracrine factors. The oocyte secretes powerful mitogens, such as growth differentiation factor 9 (GDF9), that regulate granulosa cell proliferation, metabolism, steroidogenesis and differentiation. This study investigated the role of the epidermal growth factor receptor (EGFR)-extracellular signal-regulated kinase 1 and 2 (ERK1/2; also known as MAPK3/1) signaling pathway on GDF9 action on granulosa cells. Results show that mitogenic action of the oocyte is prevented by pharmacological inhibition of the EGFR-ERK1/2 pathway. Importantly, EGFR-ERK1/2 activity as well as rous sarcoma oncogene family kinases (SFK) are required for signaling through SMADs, mediating GDF9, activin A and TGFbeta1 mitogenic action in granulosa cells. GDF9 could not activate ERK1/2 or affect EGF-stimulated ERK1/2 in granulosa cells. However, induction of the SMAD3-specific CAGA reporter by GDF9 in granulosa cells required active EGFR, SFKs and ERK1/2 as did GDF9-responsive gene expression. Finally, the EGFR-SFKs-ERK1/2 pathway was shown to be required for the maintenance of phosphorylation of the SMAD3 linker region. Together our results suggest that receptivity of granulosa cells to oocyte-secreted factors, including GDF9, is regulated by the level of activation of the EGFR and resulting ERK1/2 activity, through the requisite permissive phosphorylation of SMAD3 in the linker region. Our results indicate that oocyte-secreted TGFbeta-like ligands and EGFR-ERK1/2 signaling are cooperatively required for the unique granulosa cell response to the signal from oocytes mediating granulosa cell survival and proliferation and hence the promotion of follicle growth and ovulation.
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PMID:Growth differentiation factor 9 signaling requires ERK1/2 activity in mouse granulosa and cumulus cells. 2073 13


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