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Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy

ABSTRACT: Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy

PROVIDER: PRJNA562868 | ENA |

REPOSITORIES: ENA

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Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy (Knockdown Series)

Project description:BRAF V600 mutation influences cellular signaling pathways for melanoma development. Here, we show that mutated BRAF plays an essential role in the adaptive stress response following activation of general control non-derepressible 2 (GCN2) kinase. In parallel with GCN2, BRAF ensures ATF4 induction by utilizing mTOR and eIF4B as downstream regulators during nutrient stress and BRAF-targeted, therapeutic stress. Upon pharmacological BRAF inhibition, this signaling pathway exhibits temporal resistance, compared with the MEK-ERK pathway, thereby enabling transient induction of ATF4 under GCN2 activation. Notably, the prevention of GCN2 activation, using a chemical inhibitor that we identified, produces synergistic cell killing with BRAF inhibition. Thus, oncogenic BRAF can collaborate with the GCN2–ATF4 pathway, promoting stress adaptation for cell survival.

2020-04-06 | GSE136614 | GEO

Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy (Drug Treatmant Series)

2020-04-06 | GSE136613 | GEO

Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy (Knockdown Series)

Project description:Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy (Knockdown Series)

| PRJNA562870 | ENA

Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy (Drug Treatmant Series)

Project description:Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy (Drug Treatmant Series)

| PRJNA562871 | ENA

Disrupting ATF4 Expression Mechanisms Provides an Effective Strategy for BRAF-Targeted Melanoma Therapy.

Project description:BRAF V600 mutation influences cellular signaling pathways for melanoma development. However, the role of oncogenic BRAF in adaptive stress response pathways is not fully understood. Here, we show that oncogenic BRAF plays an essential role in the induction of ATF4 following the activation of general control non-derepressible 2 (GCN2) kinase during nutrient stress and BRAF-targeted, therapeutic stress. Under GCN2 activation, BRAF ensures ATF4 induction by utilizing mTOR and eIF4B as downstream regulators. In contrast to the MEK-ERK pathway, this signaling pathway remains temporarily active even during treatment with BRAF inhibitors, thereby enabling the transient induction of ATF4. We also identify a chemical compound that prevents BRAF inhibitor-induced activation of the GCN2-ATF4 pathway and produces synergistic cell killing with BRAF inhibitors. Our findings establish a collaborative relationship between oncogenic BRAF and the GCN2-ATF4 signaling pathway, which may provide a novel therapeutic approach to target the adaptive stress response.

| S-EPMC7155235 | biostudies-literature

Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-04-05 | GSE136615 | GEO

HDX-MS data on bRaf, bRaf/Cdc37 and bRaf/Cdc37/Hsp90 protein complexes

Project description:HDX-MS data on bRaf, bRaf/Cdc37 and bRaf/Cdc37/Hsp90 protein complexes

2022-01-04 | MSV000088635 | MassIVE

Effect of muscle-specific ATF4 gene knockout (ATF4 mKO) on skeletal muscle mRNA levels in aged mice.

Project description:For additional details see Ebert et al, Identification and Small Molecule Inhibition of an ATF4-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy. Quadriceps femoris muscles were harvested from 22-month-old muscle-specfic ATF4 knockout (ATF4 mKO) mice and littermate controls. mRNA levels in ATF4 mKO muscles were normalized to levels in littermate control muscles.

2015-09-03 | E-GEOD-72658 | biostudies-arrayexpress

Overexpression of ATF4 in BEAS2B cells

Project description:To determine gene expression changes induced by ATF4 overexpression, RNA was isolated from BEAS2B cells after overexpression of ATF4 or negative control. mRNA expression was profiled using Affymetrix Human Gene 1.0 ST Arrays. RNA isolated from BEAS2B cells after overexpression of ATF4 or empty vector was processed and hybridized to Affymetrix Human Gene 1.0 ST Arrays. Experiments were performed in triplicate. Data from the 6 microarrays were used for RMA normalization. RMA normalization was performed in the R statsitical environment using the affy package. A t-test was used to determine the association of gene expression with ATF4 overexpression.

2013-05-01 | E-GEOD-45949 | biostudies-arrayexpress

RNA-Seq experiment to identify genes regulated by ATF4

Project description:Activating Transcription Factor 4 (ATF4) is a transcription factor induced by the integrated stress response (ISR). This experiment is a genome-wide profiling of ATF4-dependent RNA expression in human HAP-1 cells. HAP-1 is a near-haploid human cell line that was derived from KBM-7 cells isolated from a patient with Chronic Myelogenous Leukemia. We analyzed WT and ATF4 KO cells. We induced ATF4 expression by mimicking amino acid starvation with the drug histidinol. RNA expression profiles were generated for WT and ATF4 KO HAP1 cells. ATF4 genes were mutated using Cas9 genome editing technology. Amino acid starvation was mimicked by treating WT and ATF4 KO cells with 2 mM histidinol for 24 hours, which increases ATF4 expression.

2015-08-28 | E-GEOD-69308 | biostudies-arrayexpress

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