| First Author | Huggins CJ | Year | 2013 |
| Journal | Mol Cell Biol | Volume | 33 |
| Issue | 16 | Pages | 3242-58 |
| PubMed ID | 23775115 | Mgi Jnum | J:204722 |
| Mgi Id | MGI:5538472 | Doi | 10.1128/MCB.01674-12 |
| Citation | Huggins CJ, et al. (2013) C/EBPgamma suppresses senescence and inflammatory gene expression by heterodimerizing with C/EBPbeta. Mol Cell Biol 33(16):3242-58 |
| abstractText | 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. |
