GCN2 adapts protein synthesis to scavenging-dependent growth.
Cell Syst
; 13(2): 158-172.e9, 2022 02 16.
Article
em En
| MEDLINE
| ID: mdl-34706266
ABSTRACT
Pancreatic cancer cells with limited access to free amino acids can grow by scavenging extracellular protein. In a murine model of pancreatic cancer, we performed a genome-wide CRISPR screen for genes required for scavenging-dependent growth. The screen identified key mediators of macropinocytosis, peripheral lysosome positioning, endosome-lysosome fusion, lysosomal protein catabolism, and translational control. The top hit was GCN2, a kinase that suppresses translation initiation upon amino acid depletion. Using isotope tracers, we show that GCN2 is not required for protein scavenging. Instead, GCN2 prevents ribosome stalling but without slowing protein synthesis; cells still use all of the limiting amino acids as they emerge from lysosomes. GCN2 also adapts gene expression to the nutrient-poor environment, reorienting protein synthesis away from ribosomes and toward lysosomal hydrolases, such as cathepsin L. GCN2, cathepsin L, and the other genes identified in the screen are potential therapeutic targets in pancreatic cancer.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
/
Proteínas Serina-Treonina Quinases
/
Proteínas de Saccharomyces cerevisiae
Limite:
Animals
Idioma:
En
Revista:
Cell Syst
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos