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Andrea Thiele

Publications and source records attributed to Andrea Thiele.

6 recordsLinked to original sources
PubMed2006

AU-rich elements and alternative splicing in the beta-catenin 3'UTR can influence the human beta-catenin mRNA stability.

Beta-catenin, the central player of the Wnt signaling cascade, is a well-known oncogene. The regulation of beta-catenin protein stability has been studied extensively while other mechanisms that control cellular levels of beta-catenin have hardly been addressed. In this study, we show that there are three beta-catenin mRNA splice variants that differ solely in their 3'-untranslated region (3'UTR) due to alternative splicing or retaining of an intron. The three isoforms were found to be ubiquitously expressed though in different quantities. Upon induction of the beta-catenin protein in peripheral blood mononuclear leukocytes (PBMC), the beta-catenin mRNA is induced in an isoform-specific manner. All three variants occur in the cytoplasm and contribute to the synthesis of beta-catenin acting as a transcriptional coactivator but have different cytoplasmic stabilities in Hela cells. AU-rich elements (AREs), sequence elements implicated in the regulation of mRNA stability, are found in each of the three transcripts. Surprisingly, the AREs contribute to stabilization of the beta-catenin mRNA transcripts in a splicing-dependent manner. The isoform most affected is the one found to be most induced when beta-catenin protein accumulates. These results suggest that alternative splicing and AREs can act together in regulating beta-catenin mRNA stability and thereby provide a step of controlling the cellular beta-catenin concentration.

3' Untranslated Regions↗
PubMed2005

Wnt signalling induces maturation of Paneth cells in intestinal crypts.

Wnt signalling, which is transduced through beta-catenin/TCF4, maintains the undifferentiated state of intestinal crypt progenitor cells. Mutational activation of the pathway initiates the adenomacarcinoma sequence. Whereas all other differentiated epithelial cells migrate from the crypt onto the villus, Paneth cells home towards the source of Wnt signals--that is, the crypt bottom. Here, we show that expression of a Paneth gene programme is critically dependent on TCF4 in embryonic intestine. Moreover, conditional deletion of the Wnt receptor Frizzled-5 abrogates expression of these genes in Paneth cells in the adult intestine. Conversely, adenomas in Apc-mutant mice and colorectal cancers in humans inappropriately express these Paneth-cell genes. These observations imply that Wnt signals in the crypt can separately drive a stem-cell/progenitor gene programme and a Paneth-cell maturation programme. In intestinal cancer, both gene programmes are activated simultaneously.

Animals↗
PubMed2004

Regulation of adenosine receptor subtypes during cultivation of human monocytes: role of receptors in preventing lipopolysaccharide-triggered respiratory burst.

Adenosine is a potent anti-inflammatory agent that modulates the function of cells involved in the inflammatory response. Here we show that it inhibits lipopolysaccharide (LPS)-induced formation of reactive oxygen intermediates (ROI) in both freshly isolated and cultured human monocytes. Blocking of adenosine uptake and inactivation of the adenosine-degrading enzyme adenosine deaminase enhanced the inhibitory action of adenosine, indicating that both pathways regulate the extracellular adenosine concentration. Adenosine-mediated inhibition could be reversed by XAC (xanthine amine congener), an antagonist of the adenosine receptor A(2A), and MRS 1220 [N-9-chloro-2-(2-furanyl)[1, 2, 4]-triazolo[1,5-c]quinazolin-5-benzeneacetamide], an A(3) receptor antagonist, in both cell populations, while DPCPX (1,3-dipropyl-8-cyclopentylxanthine), an A(1) receptor antagonist, had no effect. Similar to what was seen with adenosine, CGS 21680, an A(2A) and A(3) receptor agonist, and IB-MECA, a nonselective A(1) and A(3) receptor agonist, dose dependently prevented ROI formation, indicating the involvement of A(3) and probably also A(2A) in the suppressive effect of adenosine. Pretreatment of monocytes with adenosine did not lead to changes in the LPS-induced increase in intracellular calcium levels ([Ca(2+)](i)). Thus, participation of [Ca(2+)](i) in the action of adenosine seems unlikely. The adenosine-mediated suppression of ROI production was found to be more pronounced when monocytes were cultured for 18 h, a time point at which changes in the mRNA expression of adenosine receptors were observed. Most prominent was the increase in the A(2A) receptor mRNA. These data demonstrate that cultivation of monocytes is accompanied by changes in the inhibitory action of adenosine mediated by A(3) and probably also the A(2A) receptor and that regulation of adenosine receptors is an integral part of the monocyte differentiation program.

Adenine↗
PubMed2002

Cytokine modulation and suppression of liver injury by a novel analogue of thalidomide.

Thalidomide has been shown to reduce the production of tumor necrosis factor-alpha (TNF-alpha), a cytokine with deleterious pathophysiologic effects in various diseases. In search of thalidomide analogues with improved TNF-alpha inhibiting properties, 5-ethyl-1-phenyl-5-(3,4,5,6-tetrafluorophthalimido)barbituric acid (TFBA) was found to be superior to thalidomide. Besides TNF-alpha, TFBA also suppressed interleukin-6 and interleukin-10 production of isolated monocytes. The possibility that TFBA exerts its action by increasing levels of cAMP via inhibition of phosphodiesterase-4 activity was excluded. TFBA had no influence on T cell proliferation; neither did it inhibit TNF-alpha production in peripheral blood mononuclear cells stimulated by anti-CD3 monoclonal antibody. When applied to mice treated with D-galactosamine and lipopolysaccharide, TFBA prevented a rise in serum TNF-alpha, had no effect on interleukin-6 levels and led to an increase in interleukin-10 production. The changes in cytokine production observed in vitro and in vivo were reflected by similar changes in the mRNA expression. Moreover, TFBA significantly reduced liver transaminase levels in D-galactosamine/lipopolysaccharide-treated mice and thus efficiently protected the animals from liver injury. Thus, according to its properties, TFBA has the potential of modulating an immune response by acting as an anti-inflammatory agent.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2002

Novobiocin is a novel inducer of CD38 on cells of the myelomonocytic lineage.

KG-1a, HL-60 and U-937 cells, which represent different stages of myelopoiesis, showed growth retardation in response to the coumarin antibiotic novobiocin. Novobiocin was found to increase CD38 expression (in all three cell lines) and to induce differentiation along the monocytic path in HL-60 and U-937 cells but not in KG-1a cells. The increase in surface expression of CD38 was matched by NAD glycohydrolase activity and by increases in the level of specific mRNA, indicating that the gene product is active and that regulation occurs at the level of transcription or mRNA stability. Of the three cell lines tested, only the early KG-1a expressed N-cadherin, a member of Ca(2+)-dependent adhesion molecules involved in embryonic differentiation processes. In contrast to CD38, N-cadherin was slightly down-regulated pointing to a specific role of novobiocin in gene regulation.

ADP-ribosyl Cyclase↗