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Terasaka, Naoki; Hiroshima, Ayano; Koieyama, Tadashi; Ubukata, Naoko; Morikawa, Yuka; Nakai, Daisuke; Inaba, Toshimori
doi: 10.1016/S0014-5793(02)03578-0pmid: 12586329
Liver X receptors (LXRα and LXRβ) are nuclear receptors, which are important regulators of cholesterol and lipid metabolism. LXRs control genes involved in cholesterol efflux in macrophages, bile acid synthesis in liver and intestinal cholesterol absorption. LXRs also regulate genes participating in lipogenesis. To determine whether the activation of LXR promotes or inhibits development of atherosclerosis, T‐0901317, a synthetic LXR ligand, was administered to low density lipoprotein receptor (LDLR)−/− mice. T‐0901317 significantly reduced the atherosclerotic lesions in LDLR−/− mice without affecting plasma total cholesterol levels. This anti‐atherogenic effect correlated with the plasma concentration of T‐0901317, but not with high density lipoprotein cholesterol, which was increased by T‐0901317. In addition, we observed that T‐0901317 increased expression of ATP binding cassette A1 in the lesions in LDLR−/− mice as well as in mouse peritoneal macrophages. T‐0901317 also significantly induced cholesterol efflux activity in peritoneal macrophages. These results suggest that LXR ligands may be useful therapeutic agents for the treatment of atherosclerosis.
doi: 10.1016/S0014-5793(03)00002-4pmid: 12586330
We characterized the promoter activity of a medaka fish intestinal guanylyl cyclase gene, OlGC6, by assay of enzyme activity in response to various promoter–luciferase fusion gene constructs introduced into CACO‐2 cells and medaka fish embryos. A transient transfection assay of the various fusion gene constructs showed that the nucleotides between −98 and −89 in the 5′‐flanking region of the OlGC6 gene are essential for transcription of the OlGC6 gene in CACO‐2, and that the OlGC6 gene fragment between −98 and +50 is sufficient to drive gene expression in the medaka fish intestine. An electrophoretic mobility shift assay and ultraviolet (UV) cross‐linking experiments demonstrated that a nuclear protein from CACO‐2 cells and the adult medaka fish intestinal cells binds specifically to the AGACCTTTGC nucleotides in the regulatory element.
Eriksson, Kerstin; Magnusson, Peetra; Dixelius, Johan; Claesson-Welsh, Lena; Cross, Michael J
doi: 10.1016/S0014-5793(03)00003-6pmid: 12586331
The anti‐angiogenic agents angiostatin and endostatin have been shown to affect endothelial cell migration in a number of studies. We have examined the effect of these agents on intracellular signalling pathways known to regulate endothelial cell migration and proliferation/survival. Both agents inhibited fibroblast growth factor (FGF)‐, and vascular endothelial growth factor (VEGF)‐mediated migration of primary human microvascular endothelial cells and affected vascular formation in the embryoid body model. However, using phosphospecific antibodies we could not detect any effect of angiostatin or endostatin on phospholipase C‐γ (PLC‐γ), Akt/PKB, p44/42 mitogen‐activated protein kinase (MAPK), p38 MAPK and p21‐activated kinase (PAK) activity. Furthermore, using a glutathione S‐transferase (GST)‐PAK pull‐down assay, we could not detect any effect on Rac activity. We conclude that angiostatin and endostatin inhibit chemotaxis, without affecting intracellular signalling pathways known to regulate endothelial migration and proliferation/survival.
Dassler, Katrin; Kaup, Matthias; Tauber, Rudolf; Fuchs, Hendrik
doi: 10.1016/S0014-5793(03)00004-8pmid: 12586332
The human transferrin receptor (TfR) is proteolytically cleaved at R100 within the juxtamembrane stalk and to a lesser extent at an alternative site. We examined the effect of stalk mutations on human TfR shedding in transfected CHO cells. Point mutations at R100 led to an increase in alternative shedding while the R100 cleavage product was undetectable. Replacing the TfR‐stalk by the corresponding sequences from tumor necrosis factor‐α or interleukin‐6 receptor also led to TfR ectodomain shedding. These results show that cleavage at alternative sites can compensate for suppressed cleavage at the major site and inhibitor studies reveal that at least three metalloproteases are involved in the shedding process.
Hayashi, Hisaki; Ishisaki, Akira; Imamura, Toru
doi: 10.1016/S0014-5793(03)00005-Xpmid: 12586333
We previously reported that bone morphogenetic protein (BMP)‐2 augments fibroblast growth factor (FGF)‐induced neuronal differentiation of PC12 cells by selectively upregulating FGF receptor (FGFR)‐1 expression. Here we describe the underlying mechanism. BMP‐2 activated Smad proteins in PC12 cells. Overexpression of Smad7 or Smad1, inhibitory and receptor‐regulated isoforms, respectively, suppressed or enhanced BMP‐2‐induced upregulation of FGFR‐1 expression. Smad 7 also inhibited the FGF‐induced PC12 differentiation. Our findings indicate that activation of a Smad signaling pathway is required for upregulation of FGFR‐1 expression by BMP‐2 and for the synergistic induction of PC12 differentiation by BMP‐2 and FGF.
Ónody, Annamária; Zvara, Ágnes; Hackler, László; Vı́gh, László; Ferdinandy, Péter; G. Puskás, László
doi: 10.1016/S0014-5793(03)00006-1pmid: 12586334
To profile gene expression patterns involved in ischemic preconditioning, we monitored global gene expression changes by DNA microarray analysis of 3200 rat‐specific genes and by real‐time quantitative polymerase chain reaction in rat hearts. Forty‐nine genes with altered expression were found after ischemia/reperfusion as compared to control non‐ischemic hearts and 31 genes were characteristic for classic preconditioning followed by ischemia/reperfusion as compared to ischemia/reperfusion without preconditioning. Genes with altered expression due to ischemia and/or preconditioning included those controlling protein degradation, stress responses, apoptosis, metabolic enzymes, regulatory proteins, and several unknown cellular functions. Metallothionein, natriuretic peptides, coagulation factor VII, cysteine proteinase inhibitor, peroxisome proliferator activator receptor γ and myosin light chain kinase genes were previously suspected to be related to several cardiovascular diseases, however, most of these genes have not previously been shown to be related to myocardial ischemia/reperfusion. Some genes were observed to change specifically in response to preconditioning: oligoadenylate synthase, chaperonin subunit ϵ, a cGMP phosphodiesterase (PDE9A1), a secretory carrier membrane protein, an amino acid transporter, and protease 28 subunit. None of these genes has previously been shown to be involved in the mechanism of preconditioning.
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