NIH Research Festival
FARE Award Winner
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
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