Unveiling the role of C/EBPG as a Master Stress Response Regulator

FARE Award Winner

Authors

• MK Mayekar
• CJ Huggins
• N Martin
• KL Saylor
• M Gonit
• P Jailwala
• M Kasoji
• DC Haines
• OA Quinones
• PF Johnson

Abstract

The integrated stress response (ISR) regulates cellular adaptation to various stresses such as amino acid deprivation and redox imbalances. ISR upregulates the transcription factor ATF4 to activate stress-response genes through association with cis-regulatory sites known as C/EBP:ATF response elements (CAREs) as a heterodimer with a C/EBP partner whose identity remains obscure. Here we show that C/EBPG:ATF4 heterodimers are the predominant CARE-binding species in stressed cells. Similar to ATF4, C/EBPG is also necessary for resistance of MEFs to oxidative stress. Cebpg-/- MEFs show increased levels of reactive oxygen species (ROS) as a consequence of impaired glutathione biosynthesis, as seen in ATF4-deficient MEFs. C/EBPG is required for stress-induced association of ATF4 with CAREs and activation of stress-responsive genes. Also, Cebpg-/- mice show defective eye lens formation, similar to ATF4-deficient mice. Additionally, the absence of C/EBPG causes perinatal mortality due to pulmonary atelectasis which can be rescued by in utero exposure to the antioxidant, N-acetylcysteine. Furthermore, Cebpg-/- mice show reduced incidence of spontaneous solid tumors and increased incidence of B-cell lymphomas. These findings suggests that C/EBPG may be critical for cancer cells to alleviate the hypoxic and nutrient deprivation stress in solid tumors and increased levels of ROS in the absence of C/EBPG may promote genetic lesions required for lymphomagenesis. Increased expression of C/EBPG in tumors has been shown to be associated with poor patient prognosis in several clinical studies. Hence, activation of stress-responsive genes through up-regulation of C/EBPG could be used by cancer cells to mitigate high levels of stress.

Scientific Focus Area: Cancer Biology

This page was last updated on Friday, March 26, 2021