Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA290318 | ENA |
REPOSITORIES: ENA
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Project description:Stress-induced phosphoprotein 1 (STIP1), a co-chaperone that organizes other chaperones- heat shock proteins (HSP), was recently shown to be secreted by human ovarian cancer cells to induce cell proliferation. In neuronal tissues, binding to prion protein was required for STIP1 to activate the ERK (extracellular regulated MAP kinase) signaling pathways. However, in this study, we found that STIP1 stimulated cell proliferation of ovarian cancer via a bone morphogenetic protein (BMP) signaling pathway, not through the prion-ERK pathway. The STIP1 binding to a BMP receptor, ALK2 (activin A receptor, type II-like kinase 2), was necessary and sufficient to stimulate cancer cell proliferation. The binding of STIP1 to ALK2 activated the SMAD signaling pathway, leading to transcriptional activation of ID3 (inhibitor of DNA binding 3) that promotes cell proliferation. In conclusion, ovarian cancer tissues secrete STIP1 into the local environment and eventually into blood circulation of patients. In an autocrine and/or paracrine fashion, secreted STIP1 stimulates cancer cell proliferation by binding to ALK2 and activating the SMAD-ID3 signaling pathways. Elucidation of the mechanism by which STIP1 stimulates cancer cell proliferation may pave the way for developing novel therapeutic strategies for treatment of ovarian cancer. SKOV3 cell,treated without rhSTIP1 SKOV3 cell,treated with rhSTIP1 SKOV3 cell,treated without rhSTIP1-2 SKOV3 cell,treated with rhSTIP1-2
2013-03-09 | E-GEOD-36383 | biostudies-arrayexpress
Project description:About 50% of human malignancies exhibit unregulated signalling through the Ras-ERK1/2 (ERK) pathway, as a consequence of activating mutations in members of Ras and Raf families. However, the quest for alternative Ras-ERK pathway-directed therapies is desirable. Upon phosphorylation ERK dimerize. We had previously demonstrated that dimerization is essential for ERK extranuclear but not nuclear signaling. Furthermore, by molecular biology approaches, we showed that specifically inhibiting ERK extranuclear component, by impeding ERK dimerization, is sufficient for curtailing tumor progression. Here, we have identified a small molecule inhibitor for ERK dimerization in vitro and in vivo that, without affecting ERK phosphorylation, prevents tumorigenesis driven by Ras-ERK pathway oncogenes, both in cellular and animal models. Importantly, this compound is unaffected by resistance-acquisition processes that hamper “classical” Ras-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two novel concepts in cancer therapy: 1) The blockade of sublocalization-specific sub-signals, rather than total signals, as a means of effectively counteracting oncogenic Ras-ERK signaling. 2) Targeting regulatory protein-protein interactions such as dimerization, rather than catalytic activities, within a signaling route, as an approach for producing effective anti-tumoral agents. Strategies aimed at preventing aberrant flux through this route remain an attractive option for therapeutic intervention in cancer. In this respect, drugs inhibiting the kinase activities of BRaf and MEK have yielded promising results. A375p cells treated with10 μM of either DEL22379, SCH772984 or DMSO as a control for two hours. mRNA from A375p cells was extrated using RNeasy mini kit (Qiagen, Germany) according to the manufacturer's instructions. Cells were previously treated with10 μM of either DEL22379, SCH772984 or DMSO as a control for two hours.
2015-04-24 | E-GEOD-68230 | biostudies-arrayexpress
Project description:Kynureninase is a member of a large family of catalytically diverse but structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes known as the aspartate aminotransferase superfamily or alpha-family. The Homo sapiens and other eukaryotic constitutive kynureninases preferentially catalyze the hydrolytic cleavage of 3-hydroxy-l-kynurenine to produce 3-hydroxyanthranilate and l-alanine, while l-kynurenine is the substrate of many prokaryotic inducible kynureninases. The human enzyme was cloned with an N-terminal hexahistidine tag, expressed, and purified from a bacterial expression system using Ni metal ion affinity chromatography. Kinetic characterization of the recombinant enzyme reveals classic Michaelis-Menten behavior, with a Km of 28.3 +/- 1.9 microM and a specific activity of 1.75 micromol min-1 mg-1 for 3-hydroxy-dl-kynurenine. Crystals of recombinant kynureninase that diffracted to 2.0 A were obtained, and the atomic structure of the PLP-bound holoenzyme was determined by molecular replacement using the Pseudomonas fluorescens kynureninase structure (PDB entry 1qz9) as the phasing model. A structural superposition with the P. fluorescens kynureninase revealed that these two structures resemble the "open" and "closed" conformations of aspartate aminotransferase. The comparison illustrates the dynamic nature of these proteins' small domains and reveals a role for Arg-434 similar to its role in other AAT alpha-family members. Docking of 3-hydroxy-l-kynurenine into the human kynureninase active site suggests that Asn-333 and His-102 are involved in substrate binding and molecular discrimination between inducible and constitutive kynureninase substrates.
| S-EPMC2531291 | biostudies-literature
Project description:Human adult mesenchymal stromal cells (hMSC) have the potential to differentiate into chondrogenic, adipogenic or osteogenic lineages, providing a potential source for tissue regeneration. An important issue for efficient bone regeneration is to identify factors that can be targeted to promote the osteogenic potential of hMSCs. Using transcriptomic analysis, we found that integrin alpha5 (ITGA5) expression is upregulated during dexamethasone-induced hMSCs osteoblast differentiation. Gain-of-function studies showed that ITGA5 promotes the expression of osteoblast phenotypic markers as well as in vitro osteogenesis in hMSCs. Downregulation of endogenous ITGA5 using shRNA blunted osteoblast marker expression and osteogenic differentiation. Pharmacological and molecular analyses showed that the enhanced hMSCs osteoblast differentiation induced by ITGA5 was mediated by activation of FAK/ERK1/2-MAPKs and PI3K signaling pathways. Remarkably, activation of ITGA5 using a specific antibody that primes the integrin or a peptide that specifically activates ITGA5 was sufficient to enhance ERK1/2-MAPKs and PI3K signaling and to promote osteoblast differentiation and osteogenic capacity of hMSCs. We also demonstrate that hMSCs engineered to over-express ITGA5 exhibited a marked increase in their osteogenic potential in vivo. These findings not only reveal that ITGA5 is required for osteoblast differentiation of adult human MSCs but also provide a novel targeted strategy using ITGA5 agonists to promote the osteogenic capacity of hMSCs, which may be used for tissue regeneration in bone disorders where the recruitment or capacity of MSCs is compromised. Experiment Overall Design: Gene expression profiles were generated from bone marrow MSC before and 1, 3 and 7 days after stimulation with 10E-7M dexamethasone to study the early molecular processes of osteogenic differentiation. 3 replicates per timepoint.
2009-09-18 | E-GEOD-18043 | biostudies-arrayexpress
Project description:RNA extracted at 240min. Samples are rRNA depleted. Expression measurement of Homo sapiens genes.
2019-07-31 | GSE114179 | GEO
Project description:Heat shock proteins are highly conserved proteins that, when produced intracellularly, protect stress exposed cells. It has been suggested that extracellular Hsp70 has both protective and deleterious effects. Our study showed eHSP70 increased the ALP activity, promoted mineralization and up-regulated osteogenesis-related markers. We used microarrays to determine the differentially expressed genes and identify revelant pathways through pathway enrichment analysis. hMSCs were selected for RNA extraction and hybridization on Affymetrix microarrays after 3-day culture. The experimental group was treated with HSP70 (200ng/ml) during osteogenic differentiation and control group without it.
2016-07-03 | E-GEOD-71080 | biostudies-arrayexpress