title: C/EBPγ Is a Critical Regulator of Cellular Stress Response Networks through Heterodimerization with ATF4.
abstract: The integrated stress response (ISR) controls cellular adaptations to nutrient deprivation, redox imbalances, and endoplasmic reticulum (ER) stress. ISR genes are upregulated in stressed cells, primarily by the bZIP transcription factor ATF4 through its recruitment to cis-regulatory C/EBP:ATF response elements (CAREs) together with a dimeric partner of uncertain identity. Here, we show that C/EBPγ:ATF4 heterodimers, but not C/EBPβ:ATF4 dimers, are the predominant CARE-binding species in stressed cells. C/EBPγ and ATF4 associate with genomic CAREs in a mutually dependent manner and coregulate many ISR genes. In contrast, the C/EBP family members C/EBPβ and C/EBP homologous protein (CHOP) were largely dispensable for induction of stress genes. Cebpg(-/-) mouse embryonic fibroblasts (MEFs) proliferate poorly and exhibit oxidative stress due to reduced glutathione levels and impaired expression of several glutathione biosynthesis pathway genes. Cebpg(-/-) mice (C57BL/6 background) display reduced body size and microphthalmia, similar to ATF4-null animals. In addition, C/EBPγ-deficient newborns die from atelectasis and respiratory failure, which can be mitigated by in utero exposure to the antioxidant, N-acetyl-cysteine. Cebpg(-/-) mice on a mixed strain background showed improved viability but, upon aging, developed significantly fewer malignant solid tumors than WT animals. Our findings identify C/EBPγ as a novel antioxidant regulator and an obligatory ATF4 partner that controls redox homeostasis in normal and cancerous cells.
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Huggins
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
authors.forename: Manasi K
authors.initials: MK
authors.lastname: Mayekar
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Martin
authors.affiliation: Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Saylor
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
authors.forename: Mesfin
authors.initials: M
authors.lastname: Gonit
authors.affiliation: Advanced Biomedical Computing Center, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Parthav
authors.initials: P
authors.lastname: Jailwala
authors.affiliation: Advanced Biomedical Computing Center, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Manjula
authors.initials: M
authors.lastname: Kasoji
authors.affiliation: Pathology/Histotechnology Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Diana C
authors.initials: DC
authors.lastname: Haines
authors.affiliation: DMS, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Octavio A
authors.initials: OA
authors.lastname: Quiñones
authors.affiliation: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA johnsope@mail.nih.gov.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Johnson
mesh_terms: D051701:Activating Transcription Factor 4 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D055503:Protein Multimerization; D020218:Response Elements; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C497250:Ddit3 protein, mouse; C068794:Cebpg protein, mouse; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D005978:Glutathione