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

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

PROVIDER: PRJNA562871 | 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

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

| PRJNA562868 | 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

Braf

Project description:Mus musculus Braf, Braf transforming gene [Source:MGI Symbol;Acc:MGI:88190], is differentially expressed in 105 experiment(s);

| ENSMUSG00000002413 | ExpressionAtlas

Braf

Project description:Mus musculus Braf, Braf transforming gene [Source:MGI Symbol;Acc:MGI:88190], is expressed in 45 baseline experiment(s);

| ENSMUSG00000002413 | ExpressionAtlas

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

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