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| 2. |
- Franzén, Åsa, 1972-
(författare)
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Regulatory Effects of TGF-β Superfamily Members on Normal and Neoplastic Thyroid Epithelial Cells
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Thyroid growth and function is partly regulated by growth factors binding to receptors on the cell surface. In the present thesis, the transforming growth factor-β (TGF-β) superfamily members have been studied for their role in regulation of growth and differentiation of both normal and neoplastic thyroid epithelial cells.TGF-β1 is a negative regulator of thyrocyte growth and function. However, the importance of other TGF-β superfamily members has not been fully investigated. TGF-β1, activin A, bone morphogenetic protein (BMP)-7 and their receptors were found to be expressed in porcine thyrocytes. In addition to TGF-β1, activin A was also found to be a negative regulator of thyroid growth and function, and both stimulated phosphorylation and nuclear translocation of Smad proteins. Furthermore, TGF-β1 and epidermal growth factor (EGF) demonstrated a synergistic negative effect on thyrocyte differentiation. Simultaneous addition of the two factors resulted in a loss of the transepithelial resistance and expression of the epithelial marker E-cadherin. This was followed by a transient expression of N-cadherin.Despite the extremely malignant character of anaplastic thyroid carcinoma (ATC) tumor cells, established cell lines are still responsive to TGF-β1. A majority of the cell lines were also found to be growth inhibited by BMP-7. BMP-7 induced cell cycle arrest of the ATC cell line HTh 74 in a dose- and cell density-dependent manner. This was associated with upregulation of p21CIP1 and p27KIP1, decreased cyclin-dependent kinase (Cdk) activity and hypophosphorylation of the retinoblastoma protein (pRb). TGF-β1, and to some extent also BMP-7, induced the expression of N-cadherin and matrix metalloproteinase (MMP)-2 and -9. Stimulation of HTh 74 cells with TGF-β1 increased the migration through a reconstituted basement membrane indicating an increased invasive phenotype of the cells.Taken together, these data show that TGF-β superfamily members not only affect growth and function of normal thyroid follicle cells but may also, in combination with EGF, play a role in cell dedifferentiation. This study additionally suggests that the TGF-β superfamily members may be important for the invasive properties of ATC cells.
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| 3. |
- Goumans, MJ, et al.
(författare)
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Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors
- 2002
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Ingår i: EMBO Journal. - : Wiley. - 1460-2075. ; 21:7, s. 1743-1753
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Tidskriftsartikel (refereegranskat)abstract
- The generation of mice lacking specific components of the transforming growth factor-beta (TGF-beta) signal tranduction pathway shows that TGF-beta is a key player in the development and physiology of the cardiovascular system. Both pro- and anti-angiogenic properties have been ascribed to TGF-beta, for which the molecular mechanisms are unclear. Here we report that TGF-beta can activate two distinct type I receptor/Smad signalling pathways with opposite effects. TGF-beta induces phosphorylation of Smad1/5 and Smad2 in endothelial cells and these effects can be blocked upon selective inhibition of ALK1 or ALK5 expression, respectively. Whereas the TGF-beta/ALK5 pathway leads to inhibition of cell migration and proliferation, the TGF-beta/ ALK1 pathway induces endothelial cell migration and proliferation. We identified genes that are induced specifically by TGF-beta-mediated ALK1 or ALK5 activation. Id1 was found to mediate the TGF-beta/ALK1-induced (and Smad-dependent) migration, while induction of plasminogen activator inhibitor-1 by activated ALK5 may contribute to the TGF-beta-induced maturation of blood vessels. Our results suggest that TGF-beta regulates the activation state of the endothelium via a fine balance between ALK5 and ALK1 signalling.
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| 5. |
- Rosendahl, Alexander, et al.
(författare)
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Activation of bone morphogenetic protein/Smad signaling in bronchial epithelial cells during airway inflammation
- 2002
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Ingår i: American Journal of Respiratory Cell and Molecular Biology. - : American Thoracic Society. - 1044-1549 .- 1535-4989. ; 27:2, s. 160-169
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Tidskriftsartikel (refereegranskat)abstract
- Bone morphogenetic proteins (BMPs) are pleiotropic secreted proteins, structurally related to transforming growth factor (TGF)-beta and activins. BMPs play pivotal roles in the regulation of embryonic lung development and branching of airways and have recently been considered to influence inflammatory processes in adults due to their chemotactic activity on fibroblasts, myocytes, and inflammatory cells. In this study, we have investigated the possible involvement of BMPs in a model of experimental allergic-airway inflammation in situ using antibodies that detect activated Smad proteins, and have monitored the modulation of BMP ligands during the inflammatory response. Inflamed bronchial epithelial cells and a few scattered alveolar cells expressed levels of phosphorylated Smad1 (pSmad1/5), indicative of active BMP/Smad signaling. This was in contrast to healthy epithelium, which was devoid of immunoreactivity. A mechanistic explanation for increased pSmad1/5 staining during inflammation was provided by the upregulated expression of all the BMP type I receptors, i.e., activin receptor-like kinase (ALK)2, ALK3, and ALK6, in the inflamed bronchial epithelial cells. Furthermore, the mRNA and protein profiles for BMP ligands were significantly altered during airway inflammation with induction of BMP2, BMP4, and BMP6, and downregulation of BMP5 and BMP7. Collectively, our data demonstrate for the first time active BMP/Smad signaling during airway inflammation in bronchial epithelial cells and thus raise the possibility that BMPs could play a determining role in respiratory pathophysiology.
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| 6. |
- Rosendahl, Alexander, et al.
(författare)
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Activation of the TGF-beta/activin-Smad2 pathway during allergic airway inflammation
- 2001
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Ingår i: American Journal of Respiratory Cell and Molecular Biology. - : American Thoracic Society. - 1044-1549 .- 1535-4989. ; 25:1, s. 60-68
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Tidskriftsartikel (refereegranskat)abstract
- Changes in the levels of transforming growth factor (TGF)-beta cytokines or receptors observed during the progression of several inflammatory and fibrotic disorders have been used to implicate these cytokines in the pathophysiology of these diseases. Although correlative, these studies were inconclusive because they were unable to demonstrate actual continuous TGF-beta-mediated signaling in the involved tissues. We reasoned that the phosphorylation state and subcellular localization of Smad2, the intracellular effector of TGF-beta/activin-mediated signaling, could be used as a marker of active signaling mediated by these cytokines in situ. We therefore used an experimental model of ovalbumin-induced allergic airway inflammation and were able to demonstrate a dramatic increase in the numbers of bronchial epithelial, alveolar, and infiltrating inflammatory cells expressing nuclear phosphorylated Smad2 within the allergen-challenged lungs. This was accompanied by strong upregulation of the activin receptor ALK-4/ActR-IB and redistribution of the TGF-beta responsive ALK-5/TbetaR-I. Although levels of TGF-beta1, TGF-beta2, and TGF-beta3 messenger RNA (mRNA) were marginally altered, the level of activin mRNA was strongly upregulated during the inflammatory response. Our data illustrate the usefulness of antiphosphorylated Smad antibodies in demonstrating active TGF- beta/activin-mediated signaling in vivo and strongly suggest that activin/Smad-mediated signaling could be a critical contributor in the pathophysiology of allergic pulmonary diseases.
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| 7. |
- Tzoanopoulos, D, et al.
(författare)
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Low expression of interferon regulatory factor-1 and identification of novel exons skipping in patients with chronic myeloid leukaemia
- 2002
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048. ; 119:1, s. 46-53
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Tidskriftsartikel (refereegranskat)abstract
- Chronic myeloid leukaemia (CML) is a malignant clonal disorder of the haematopoietic stem cell. Treatment of CML patients with interferon alpha (IFN-alpha) has induced haematological and cytogenetic remission. Interferons transcriptionally activate target genes through the JAK-STAT and interferon regulated factors (IRFs) family pathways. Interferon regulated factor-1 (IRF-1) is a transcriptional activator of genes critical for cell growth, differentiation and apoptosis. The skipping of exons 2 or 2 and 3 of IRF-1 in patients with myelodysplastic syndromes and acute myelogenous leukaemia suggests that this factor may have a critical role in leukaemogenesis. The role of IRF-1 in CML is currently unknown. Therefore, mutational analysis of IRF-1 was performed and its expression pattern was also studied in CML patients. We studied IRF-1 in peripheral blood mononuclear cells of 21 patients in chronic phase CML. No point mutations were identified at the cDNA level. Surprisingly, fourfold reduction of full-length IRF-1 mRNA expression was established in 17/21 patients compared with normal individuals. Low expression of full-length IRF-1 was observed in conjunction with high levels of aberrantly spliced mRNAs, reported for the first time. In three patients who were also analysed during blastic transformation, further reduction of full-length IRF-1 mRNA was observed. These findings demonstrate that, in CML patients, IRF-1 can produce high levels of aberrant spliced mRNAs with subsequent reduction in the levels of full-length IRF-1 mRNA. This observation is consistent with the notion that exon skipping may constitute another mechanism of tumour suppressor gene inactivation in this disease.
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| 8. |
- Valdimarsdottir, Gudrun, et al.
(författare)
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Stimulation of id1 expression by bone morphogenetic protein is sufficient and necessary for bone morphogenetic protein-induced activation of endothelial cells.
- 2002
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Ingår i: Circulation. - 1524-4539. ; 106:17, s. 2263-2270
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Tidskriftsartikel (refereegranskat)abstract
- Background— Bone morphogenetic proteins (BMPs) are multifunctional proteins that regulate the proliferation, differentiation, and migration of a large variety of cell types. Like other members of the transforming growth factor-ß family, BMPs elicit their cellular effects through activating specific combinations of type I and type II serine/threonine kinase receptors and their downstream effector proteins, which are termed Smads. In the present study, we investigated BMP receptor/Smad expression and signaling in endothelial cells (ECs) and examined the effects of BMP on EC behavior. Methods and Results— Immunohistochemical analysis of tissue sections of human colon and mouse heart and aorta showed that BMP receptors are expressed in ECs in vivo. Bovine aortic ECs and mouse embryonic ECs were found to express BMP receptors and their Smads. BMP receptor activation induced the phosphorylation of specific Smad proteins and promoted EC migration and tube formation. Id1 was identified as a BMP/Smad target in ECs. Ectopic expression of Id1 mimicked BMP-induced effects. Importantly, specific interference with Id1 expression blocked BMP-induced EC migration. Conclusions— The BMP/Smad pathway can potently activate the endothelium. Id1 expression is strongly induced by BMP in ECs. Ectopic expression of Id1 induces EC migration and tube formation. Moreover, Id1 played a critical role in mediating BMP-induced EC migration.
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| 10. |
- Xie, Xiao-Qi, et al.
(författare)
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AML and Ets proteins regulate the I alpha1 germ-line promoter.
- 1999
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Ingår i: European Journal of Immunology. - 0014-2980 .- 1521-4141. ; 29:2, s. 488-498
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Tidskriftsartikel (refereegranskat)abstract
- The immunoglobulin heavy chain (IgH) class switch recombination of B lymphocytes preferentially targets unrearranged IgH genes that have already been rendered transcriptionally active. Transcription of the germ-line IgH genes is controlled by intervening (I) regions upstream of their switch regions. The I alpha1 promoter activates transcription of the human germ-line C alpha1 gene for IgA1 and mediates the transforming growth factor (TGF)-beta1 responsiveness of this locus. Here we show that the I alpha1 promoter contains several binding sites for the AML/PEBP2/CBF family of transcription factors and that AML and Ets proteins are major regulators of the basal and TGF-beta-inducible promoter activity. Our data constitute a starting point for studies to elucidate the molecular mechanism by which TGF-beta regulates IgA production.
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