Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
PLoS Genet ; 12(12): e1006518, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27977682

ABSTRACT

The unfolded protein response (UPR) regulates cell fate following exposure of cells to endoplasmic reticulum stresses. PERK, a UPR protein kinase, regulates protein synthesis and while linked with cell survival, exhibits activities associated with both tumor progression and tumor suppression. For example, while cells lacking PERK are sensitive to UPR-dependent cell death, acute activation of PERK triggers both apoptosis and cell cycle arrest, which would be expected to contribute tumor suppressive activity. We have evaluated these activities in the BRAF-dependent melanoma and provide evidence revealing a complex role for PERK in melanoma where a 50% reduction is permissive for BrafV600E-dependent transformation, while complete inhibition is tumor suppressive. Consistently, PERK mutants identified in human melanoma are hypomorphic with dominant inhibitory function. Strikingly, we demonstrate that small molecule PERK inhibitors exhibit single agent efficacy against BrafV600E-dependent tumors highlighting the clinical value of targeting PERK.


Subject(s)
Melanoma/genetics , Proto-Oncogene Proteins B-raf/genetics , Tumor Suppressor Proteins/genetics , eIF-2 Kinase/genetics , Apoptosis/drug effects , Apoptosis/genetics , Cell Cycle Checkpoints , Cell Line, Tumor , Cell Transformation, Neoplastic/drug effects , Endoplasmic Reticulum/genetics , Endoplasmic Reticulum/pathology , Gene Dosage/genetics , Haploinsufficiency/genetics , Humans , Melanoma/drug therapy , Melanoma/pathology , Mutation , Signal Transduction/drug effects , Signal Transduction/genetics , Small Molecule Libraries/administration & dosage , Tumor Suppressor Proteins/biosynthesis , Unfolded Protein Response/genetics , eIF-2 Kinase/antagonists & inhibitors , eIF-2 Kinase/biosynthesis
SELECTION OF CITATIONS
SEARCH DETAIL
...