Expression data from EGF-stimulated A431 cells with or without Gefitinib treatment
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE153114 | GEO | 2020/06/24
REPOSITORIES: GEO
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Project description:Expression data from EGF-stimulated A431 cells with or without Gefitinib treatment
| PRJNA641441 | ENA
Project description:Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), induces substantial clinical responses for non-small cell lung cancer (NSCLC) cells harboring EGFR activating mutations, but most of them invariably develop resistance. By generating a gefitinib resistance (PC9GR) from a human NSCLC-derived drug sensitive cell line (PC9), we studied differences of transcription dynamics between them by the aid of a computational decoupling of hidden regulatory signals from time course gene expression profiles. Given a collection of transcription factors (TFs) and their regulatory targets, the method captured temporally-synchronized shifts in evolving expression of target genes sharing each TF regulatory unit, and drew underlying regulatory signals. The analysis identified sterol regulatory element binding protein 1 (SREBP-1) as a key regulatory agent that facilitates the maintenance of drug tolerance, involving transcription controls of a G1-specific cyclin dependent kinase inhibitor whose expression was specifically elevated in PC9, but in turn, reduced in PC9GR Gefitinib-resistance cell line (PC9GR) was established derived from lung adenocarcinoma cell line PC9. PC9 cells and PC9GR cells were treated with the four different conditions, control (No treatment), EGF-treatment, gefitinib-treatment, and both gefitinib and EGF-treatment. In each condition, the gene expression was measured at 26 time points during 24 hrs.
| S-ECPF-GEOD-34228 | biostudies-other
Project description:Although many proteins have been shown to participate in ligand-stimulated endocytosis of EGF receptor (EGFR), the adaptor protein responsible for interaction of activated EGFR with endocytic machinery remains elusive. We show here that EGF stimulates transient tyrosine phosphorylation of Tom1L1 by the Src family kinases, resulting in transient interaction of Tom1L1 with the activated EGFR bridged by Grb2 and Shc. Cytosolic Tom1L1 is recruited onto the plasma membrane and subsequently redistributes into the early endosome. Mutant forms of Tom1L1 defective in Tyr-phosphorylation or interaction with Grb2 are incapable of interaction with EGFR. These mutants behave as dominant-negative mutants to inhibit endocytosis of EGFR. RNAi-mediated knockdown of Tom1L1 inhibits endocytosis of EGFR. The C-terminal tail of Tom1L1 contains a novel clathrin-interacting motif responsible for interaction with the C-terminal region of clathrin heavy chain, which is important for exogenous Tom1L1 to rescue endocytosis of EGFR in Tom1L1 knocked-down cells. These results suggest that EGF triggers a transient Grb2/Shc-mediated association of EGFR with Tyr-phosphorylated Tom1L1 to engage the endocytic machinery for endocytosis of the ligand-receptor complex.
| S-EPMC2756567 | biostudies-literature
Project description:Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), induces substantial clinical responses for non-small cell lung cancer (NSCLC) cells harboring EGFR activating mutations, but most of them invariably develop resistance. By generating a gefitinib resistance (PC9GR) from a human NSCLC-derived drug sensitive cell line (PC9), we studied differences of transcription dynamics between them by the aid of a computational decoupling of hidden regulatory signals from time course gene expression profiles. Given a collection of transcription factors (TFs) and their regulatory targets, the method captured temporally-synchronized shifts in evolving expression of target genes sharing each TF regulatory unit, and drew underlying regulatory signals. The analysis identified sterol regulatory element binding protein 1 (SREBP-1) as a key regulatory agent that facilitates the maintenance of drug tolerance, involving transcription controls of a G1-specific cyclin dependent kinase inhibitor whose expression was specifically elevated in PC9, but in turn, reduced in PC9GR
2014-01-01 | GSE34228 | GEO
Project description:RNA sequencing of A431 cell line samples before and after gefitinib treatment, at 0, 2, 6 and 24 hours, was performed in order to characterize the cell line's early and late response to this drug, and to compare against proteomics (mass spectrometry) characterization of the cell line using the same setup. These data were used in Branca et al., HiRIEF LC-MS enables deep proteome coverage and unbiased proteogenomics., Nat Methods. 2014 Jan;11(1):59-62 (doi: 10.1038/nmeth.2732).
2016-12-01 | E-MTAB-5285 | biostudies-arrayexpress
Project description:Phosphoproteomic analysis of EGF stimulated MCF7 cells. This dataset is the basis for the development of modeling of signaling networks. A fundamental challenge in biology is to delineate the signaling pathways that govern cellular responses to genetic and environmental cues. Phosphoproteomics is an emerging technology that provides key data on activity levels of proteins under conditions of interest. However, the interpretation of these data is hampered by the lack of methods that can translate site-specific information into global maps of active proteins and signaling networks. To meet this challenge, we propose PHOTON, a method for integrating phosphorylation data with protein-protein interaction networks to identify active proteins and pathways and pinpoint functional phosphosites. We demonstrate the utility of PHOTON by applying it to interpret existing and novel phosphoproteomic datasets related to EGF and insulin responses. PHOTON substantially outperforms the widely-used cutoff approach, providing highly reproducible predictions that are more in line with current biological knowledge
2016-12-06 | PXD005032 | Pride
Project description:Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), induces substantial clinical responses for non-small cell lung cancer (NSCLC) cells harboring EGFR activating mutations, but most of them invariably develop resistance. By generating a gefitinib resistance (PC9GR) from a human NSCLC-derived drug sensitive cell line (PC9), we studied differences of transcription dynamics between them by the aid of a computational decoupling of hidden regulatory signals from time course gene expression profiles. Given a collection of transcription factors (TFs) and their regulatory targets, the method captured temporally-synchronized shifts in evolving expression of target genes sharing each TF regulatory unit, and drew underlying regulatory signals. The analysis identified sterol regulatory element binding protein 1 (SREBP-1) as a key regulatory agent that facilitates the maintenance of drug tolerance, involving transcription controls of a G1-specific cyclin dependent kinase inhibitor whose expression was specifically elevated in PC9, but in turn, reduced in PC9GR Gefitinib-resistance cell line (PC9GR) was established derived from lung adenocarcinoma cell line PC9. PC9 cells and PC9GR cells were treated with the four different conditions, control (No treatment), EGF-treatment, gefitinib-treatment, and both gefitinib and EGF-treatment. In each condition, the gene expression was measured at 26 time points during 24 hrs.
2014-01-01 | E-GEOD-34228 | biostudies-arrayexpress
Project description:Epidermal growth factor (EGF)-mediated activation of EGF receptors (EGFRs) has become an important target in drug development due to the implication of EGFR-mediated cellular signaling in cancer development. While various in vitro approaches are developed for monitoring EGF-EGFR interactions, they have several limitations. Herein, we describe a live cell-based sensor system that can be used to monitor the interaction of EGF and EGFR as well as the subsequent signaling events. The design of the EGF-detecting sensor cells is based on the split-intein-mediated conditional protein trans-cleavage reaction (CPC). CPC is triggered by the presence of the target (EGF) to activate a signal peptide that translocates the fluorescent cargo to the target cellular location (mitochondria). The developed sensor cell demonstrated excellent sensitivity with a fast response time. It was also successfully used to detect an agonist and antagonist of EGFR (transforming growth factor-α and Cetuximab, respectively), demonstrating excellent specificity and capability of screening the analytes based on their function. The usage of sensor cells was then expanded from merely detecting the presence of target to monitoring the target-mediated signaling cascade, by exploiting previously developed Ca2+-detecting sensor cells. These sensor cells provide a useful platform for monitoring EGF-EGFR interaction, for screening EGFR effectors, and for studying downstream cellular signaling cascades.
| S-EPMC10045995 | biostudies-literature
Project description:RNA-seq of A431 cell line after gefitinib treatment
| PRJEB18261 | ENA
Project description:The existence of an in-frame deletion mutant correlates with the sensitivity of lung cancers to EGFR (epidermal growth factor receptor)-targeted tyrosine kinase inhibitors. We reported previously that the in-frame 15-bp deletional mutation (delE746-A750 type deletion) was constitutively active in cells. Kinetic parameters are important for characterizing an enzyme; however, it remains unclear whether the kinetic parameters of deletion mutant EGFR are similar to those of wild-type EGFR. We analysed autophosphorylation in response to ATP and inhibition of gefitinib for deletion mutant EGFR and wild-type EGFR. Kinetic studies, examining autophosphorylation, were carried out using EGFR fractions extracted from 293-pDelta15 and 293-pEGFR cells transfected with deletion mutant EGFR and wild-type EGFR respectively. We demonstrated the difference in activities between unstimulated wild-type (K(m) for ATP=4.0+/-0.3 microM) and mutant EGFR (K(m) for ATP=2.5+/-0.2 microM). There was no difference in K(m) values between EGF-stimulated wild-type EGFR (K(m) for ATP=1.9+/-0.1 microM) and deletion mutant EGFR (K(m) for ATP=2.2+/-0.2 microM). These results suggest that mutant EGFR is active without ligand stimulation. The K(i) value for gefitinib of the deletion mutant EGFR was much lower than that of wild-type EGFR. These results suggest that the deletion mutant EGFR has a higher affinity for gefitinib than wild-type EGFR.
| S-EPMC1533307 | biostudies-other