The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation.

ABSTRACT: The transcription factor ATF4 regulates the expression of genes involved in amino acid metabolism, redox homeostasis and ER stress responses, and it is overexpressed in human solid tumours, suggesting that it has an important function in tumour progression. Here, we report that inhibition of ATF4 expression blocked proliferation and survival of transformed cells, despite an initial activation of cytoprotective macroautophagy. Knockdown of ATF4 significantly reduced the levels of asparagine synthetase (ASNS) and overexpression of ASNS or supplementation of asparagine in trans, reversed the proliferation block and increased survival in ATF4 knockdown cells. Both amino acid and glucose deprivation, stresses found in solid tumours, activated the upstream eukaryotic initiation factor 2alpha (eI

SUBMITTER: Ye J 

PROVIDER: S-EPMC2892366 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature