title: C/EBPγ suppresses senescence and inflammatory gene expression by heterodimerizing with C/EBPβ.
abstract: C/EBPβ is an important regulator of oncogene-induced senescence (OIS). Here, we show that C/EBPγ, a heterodimeric partner of C/EBPβ whose biological functions are not well understood, inhibits cellular senescence. Cebpg(-/-) mouse embryonic fibroblasts (MEFs) proliferated poorly, entered senescence prematurely, and expressed a proinflammatory gene signature, including elevated levels of senescence-associated secretory phenotype (SASP) genes whose induction by oncogenic stress requires C/EBPβ. The senescence-suppressing activity of C/EBPγ required its ability to heterodimerize with C/EBPβ. Covalently linked C/EBPβ homodimers (β∼β) inhibited the proliferation and tumorigenicity of Ras(V12)-transformed NIH 3T3 cells, activated SASP gene expression, and recruited the CBP coactivator in a Ras-dependent manner, whereas γ∼β heterodimers lacked these capabilities and efficiently rescued proliferation of Cebpg(-/-) MEFs. C/EBPβ depletion partially restored growth of C/EBPγ-deficient cells, indicating that the increased levels of C/EBPβ homodimers in Cebpg(-/-) MEFs inhibit proliferation. The proliferative functions of C/EBPγ are not restricted to fibroblasts, as hematopoietic progenitors from Cebpg(-/-) bone marrow also displayed impaired growth. Furthermore, high CEBPG expression correlated with poorer clinical prognoses in several human cancers, and C/EBPγ depletion decreased proliferation and induced senescence in lung tumor cells. Our findings demonstrate that C/EBPγ neutralizes the cytostatic activity of C/EBPβ through heterodimerization, which prevents senescence and suppresses basal transcription of SASP genes.
authors.affiliation: Laboratory of Cancer Prevention, Center for Cancer Research, NCI-Frederick, Frederick, Maryland, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Huggins
authors.forename: Radek
authors.initials: R
authors.lastname: Malik
authors.forename: Sook
authors.initials: S
authors.lastname: Lee
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Salotti
authors.forename: Sara
authors.initials: S
authors.lastname: Thomas
authors.forename: Nancy
authors.initials: N
authors.lastname: Martin
authors.forename: Octavio A
authors.initials: OA
authors.lastname: Quiñones
authors.forename: W Gregory
authors.initials: WG
authors.lastname: Alvord
authors.forename: Mary E
authors.initials: ME
authors.lastname: Olanich
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Keller
authors.forename: Peter F
authors.initials: PF
authors.lastname: Johnson
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D055503:Protein Multimerization
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; C405462:CCAAT-enhancer-binding protein-gamma