Investigation of gene expression signature induced by Alk5TD (active type I TGF-beta receptor)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Wang SE
PROVIDER: S-ECPF-GEOD-11293 | biostudies-other | 2008 Sep
REPOSITORIES: biostudies-other
Similar Datasets
Project description:BT474 cells stably expressing Alk5TD or vector (BT474-Alk5TD and BT474-pBMN, respectively) were compared for gene expression. Genes that were differentially expressed between the two cell lines were collected as the signature induced by Alk5TD expression. Keywords: Comparison of two cell types (BT474-Alk5TD and BT474-pBMN). BT474-pBMN was used as the reference line. RNA samples extracted from the two cell lines (BT474-Alk5TD and BT474-pBMN) were differentially labeled (BT474-Alk5TD with Cy5 and BT474-pBMN with Cy3) and analyzed. The experiment was performed in triplicate with independent samples.
2008-04-29 | E-GEOD-11293 | biostudies-arrayexpress
Project description:BT474 cells stably expressing Alk5TD or vector (BT474-Alk5TD and BT474-pBMN, respectively) were compared for gene expression. Genes that were differentially expressed between the two cell lines were collected as the signature induced by Alk5TD expression. Keywords: Comparison of two cell types (BT474-Alk5TD and BT474-pBMN). BT474-pBMN was used as the reference line.
2008-04-30 | GSE11293 | GEO
Project description:TGF-beta1 is an important angiogenic factor involved in the different aspects of angiogenesis and vessel maintenance. TGF-beta signalling is mediated by the TbetaRII/ALK5 receptor complex activating the Smad2/Smad3 pathway. In endothelial cells TGF-beta utilizes a second type I receptor, ALK1, activating the Smad1/Smad5 pathway. Consequently, a perturbance of ALK1, ALK5 or TbetaRII activity leads to vascular defects. Mutations in ALK1 cause the vascular disorder hereditary hemorrhagic telangiectasia (HHT).The identification of ALK1 and not ALK5 regulated genes in endothelial cells, might help to better understand the development of HHT. Therefore, the human microvascular endothelial cell line HMEC-1 was infected with a recombinant constitutively active ALK1 adenovirus, and gene expression was studied by using gene arrays and quantitative real-time PCR analysis.After 24 hours, 34 genes were identified to be up-regulated by ALK1 signalling. Analysing ALK1 regulated gene expression after 4 hours revealed 13 genes to be up- and 2 to be down-regulated. Several of these genes, including IL-8, ET-1, ID1, HPTPeta and TEAD4 are reported to be involved in angiogenesis. Evaluation of ALK1 regulated gene expression in different human endothelial cell types was not in complete agreement. Further on, disparity between constitutively active ALK1 and TGF-beta1 induced gene expression in HMEC-1 cells and primary HUVECs was observed.Gene array analysis identified 49 genes to be regulated by ALK1 signalling and at least 14 genes are reported to be involved in angiogenesis. There was substantial agreement between the gene array and quantitative real-time PCR data. The angiogenesis related genes might be potential HHT modifier genes. In addition, the results suggest endothelial cell type specific ALK1 and TGF-beta signalling.
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Project description:Transforming growth factor beta (TGF-β) is a key factor mediating the intercellular crosstalk between the hematopoietic stem cells and their microenvironment. Here, we investigated the skeletal phenotype of transgenic mice expressing constitutively active TGF-β receptor type I under the control of Mx1-Cre (Mx1;TβRICA mice). μCT analysis showed decreased cortical thickness, and cancellous bone volume in both femurs and mandibles. Histomorphometric analysis confirmed a decrease in cancellous bone volume due to increased osteoclast number and decreased osteoblast number. Primary osteoblasts showed decreased ALP and mineralization. Constitutive TβRI activation increased osteoclast differentiation. qPCR analysis showed that Tnfsf11/Tnfrsf11b ratio, Ctsk, Sufu, and Csf1 were increased whereas Runx2, Ptch1, and Ptch2 were decreased in Mx1;TβRICA femurs. Interestingly, Gli1, Wnt3a, Sp7, Alpl, Ptch1, Ptch2, and Shh mRNA expression were reduced whereas Tnfsf11/Tnfrsf11b ratio was increased in Mx1;TβRICA mandibles. Similarly, osteoclast-related genes were increased in Mx1;TβRICA osteoclasts whereas osteoblast-related genes were reduced in Mx1;TβRICA osteoblasts. Western blot analysis indicated that SMAD2 and SMAD3 phosphorylation was increased in Mx1;TβRICA osteoblasts, and SMAD3 phosphorylation was increased in Mx1;TβRICA osteoclasts. CTSK was increased while RUNX2 and PTCH1 was decreased in Mx1;TβRICA mice. Microindentation analysis indicated decreased hardness in Mx1;TβRICA mice. Our study indicated that Mx1;TβRICA mice were osteopenic by increasing osteoclast number and decreasing osteoblast number, possibly by suppressing Hedgehog signaling pathways.
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Project description:It is unclear how quiescence is enforced in naive T cells, but activation by foreign antigens and self-antigens is allowed, despite the presence of inhibitory signals. We showed that active transforming growth factor β (TGF-β) signaling was present in naive T cells, and T cell receptor (TCR) engagement reduced TGF-β signaling during T cell activation by downregulating TGF-β type 1 receptor (TβRI) through activation of caspase recruitment domain-containing protein 11 (CARD11) and nuclear factor κB (NF-κB). TGF-β prevented TCR-mediated TβRI downregulation, but this was abrogated by interleukin-6 (IL-6). Mitigation of TCR-mediated TβRI downregulation through overexpression of TβRI in naive and activated T cells rendered T cells less responsive and suppressed autoimmunity. Naive T cells in autoimmune patients exhibited reduced TβRI expression and increased TCR-driven proliferation compared to healthy subjects. Thus, TCR-mediated regulation of TβRI-TGF-β signaling acts as a crucial criterion to determine T cell quiescence and activation.
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Project description:Regulating TGF-beta receptor presentation provides an avenue to alter a cell's responsiveness to TGF-beta. We report that activation of the Erk MAP kinase pathway decreases the TGF-beta-induced Smad3 activation due to decreased cell surface levels of the type I receptor TbetaRI, but not the type II receptor. Inhibition of TACE activity or expression enhanced the cell surface TbetaRI levels and TGF-beta-induced Smad3 and Akt activation. Accordingly, silencing TACE expression in cancer cells enhanced the TbetaRI presentation and TGF-beta responsiveness, including the antiproliferative effect of TGF-beta, and epithelial-to-mesenchymal transition. These results establish a mechanism for downregulating TGF-beta signaling through TACE activation by the Erk MAP kinase pathway and a strategy for evasion of tumor suppression and modulation of epithelial-to-mesenchymal transition during cancer progression. The decreased growth inhibition by TGF-beta, due to elevated TACE activity, complements the growth stimulation resulting from increased release of TGF-alpha family ligands.
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