Analysis of mRNA levels of GPCR and GPCR-related signaling proteins in the HEK293 cell line
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE25894 | GEO | 2011/02/01
SECONDARY ACCESSION(S): PRJNA142457
REPOSITORIES: GEO
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Project description:Measurements of mRNA levels for non-chemosensory GPCRs, G proteins and selected G protein targets. HEK293 cell line, 4 replicates. Overall data set includes mRNA levels for ~24,000 genes.
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Project description:Measurements of mRNA levels for non-chemosensory GPCRs, G proteins and selected G protein targets.
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Project description:Osmosensors play essential roles in maintaining body fluidic balance in the animal kingdom. However, the molecular identities of osmosensors in mammals are still elusive. TRP channels have been proposed to be candidate osmosensors, but their roles in regulating body fluid homeostasis are still controversial. The major difficulty in identifying osmosensors in animals, is in part because of the lack of efficient screening methods. Here, we designed and conducted a neuronal activity-based genetic screen to identify the first osmosensors in animal kingdom using C. elegans. Previous studies show G proteins are required for C. elegans sensing osmotic stimuli. Thus, we proposed that the osmosensors are GPCRs. To identify the GPCRs enriched in ASH neurons, which are the major osmosensing neurons, we did RNA-seq after FACS sorting for ASH. After screening the enriched GPCRs in ASH, we successfully found one GPCR, OSGR-1, functions as an osmosensor in C. elegans. We also found, its closest paralog, OSGR-2, is also an osmosensor. This is also the first shown that GPCRs are capable of sensing osmolarity, which will facilitate the identification of osmosensors in other animals.
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Project description:Acute myeloid leukemia (AML) is an aggressive and heterogenous hematological malignancy. In elderly patients, AML incidence is high and has a poor prognosis due to a lack of effective therapies. G-protein coupled receptors (GPCRs) play integral roles in physiological processes and human diseases. Particularly, one-third of adhesion GPCRs, the second largest group of GPCRs, are highly expressed in hematopoietic stem and progenitor cells or lineage cells. Therefore, we investigated the role of adhesion GPCRs in AML and whether they could be harnessed as anti-leukemia targets. Systematic screening of the impact of adhesion GPCRs on AML functionality by combined bioinformatic and functional analyses revealed high expression of ADGRE2 in AML, particularly in leukemic stem cells (LSCs), which was associated with poor patient outcomes. Silencing ADGRE2 not only exerted anti-leukemia effects in AML cell lines and AML patient-derived cells in vitro but also delayed AML progression in xenograft models in vivo. Mechanistically, ADGRE2 activated PLC-β/PKC/MEK/ERK signaling to enhance expression of AP-1 and transcriptionally drive expression of DUSP1, a protein phosphatase. DUSP1 de-phosphorylated Ser16 in the J-domain of the co-chaperone DNAJB1, which facilitated DNAJB1-HSP70 interaction and maintenance of proteostasis in AML. Finally, combined inhibition of MEK, AP-1, and DUSP1 exhibited robust therapeutic efficacy in AML xenograft mouse models. Collectively, this study deciphers the roles and mechanisms of ADGRE2 in AML and provides a promising therapeutic strategy for treating AML.
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Project description:Structural studies of glycoproteins and their complexes provide critical insights into their roles in normal physiology and disease. Most glycoproteins contain N-linked glycosylation, a key post-translation modification that critically affects protein folding and stability and the binding kinetics underlying protein interactions. However, N-linked glycosylation is often an impediment to yielding homogeneous protein preparations for structure determination by X-ray crystallography or other methods. In particular, obtaining diffraction-quality crystals of such proteins and their complexes often requires modification of both the type of glycosylation patterns and their extent. Here, we demonstrate the benefits of producing target glycoproteins in the GlycoDelete human embryonic kidney 293 cell line that has been engineered to produce N-glycans as short glycan stumps comprising N-acetylglucosamine, galactose and sialic acid. Protein fragments of human Down syndrome cell-adhesion molecule and colony-stimulating factor 1 receptor were obtained from the GlycoDelete cell line for crystallization. The ensuing reduction in the extent and complexity of N-glycosylation in both protein molecules compared with alternative glycoengineering approaches enabled their productive deployment in structural studies by X-ray crystallography. Furthermore, a third successful implementation of the GlycoDelete technology focusing on murine IL-12B is shown to lead to N-glycosylation featuring an immature glycan in diffraction-quality crystals. It is proposed that the GlycoDelete cell line could serve as a valuable go-to option for the production of homogeneous glycoproteins and their complexes for structural studies by X-ray crystallography and cryo-electron microscopy.
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