1054

CEBPG

CCAAT/enhancer binding protein (C/EBP), gamma;CEBPG;CCAAT/enhancer binding protein (C/EBP), gamma

CCAAT/enhancer-binding protein gamma|c/EBP gamma

19q13.11

protein-coding

C/EBPbeta is an important regulator of oncogene-induced senescence (OIS). Here, we show that C/EBPgamma, a heterodimeric partner of C/EBPbeta 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/EBPbeta. The senescence-suppressing activity of C/EBPgamma required its ability to heterodimerize with C/EBPbeta. Covalently linked C/EBPbeta homodimers (beta approximately beta) 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 gamma approximately beta heterodimers lacked these capabilities and efficiently rescued proliferation of Cebpg(-/-) MEFs. C/EBPbeta depletion partially restored growth of C/EBPgamma-deficient cells, indicating that the increased levels of C/EBPbeta homodimers in Cebpg(-/-) MEFs inhibit proliferation. The proliferative functions of C/EBPgamma 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/EBPgamma depletion decreased proliferation and induced senescence in lung tumor cells. Our findings demonstrate that C/EBPgamma neutralizes the cytostatic activity of C/EBPbeta through heterodimerization, which prevents senescence and suppresses basal transcription of SASP genes.