C/EBPγ Suppresses Senescence and Inflammatory Gene Expression by Heterodimerizing with C/EBPβ
C/EBPγ Suppresses Senescence and Inflammatory Gene Expression by Heterodimerizing with C/EBPβ
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DOI：
10.1128/mcb.01674-12
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发表时间：
2013-08-01
影响因子：
5.3
通讯作者：
Johnson, Peter F.
中科院分区：
文献类型：
--
作者：
Huggins, Christopher J.;Malik, Radek;Johnson, Peter F.
C/EBP β是癌基因诱导衰老（OIS）的重要调节因子。在这里，我们表明，C/EBP γ，异源二聚体的合作伙伴的C/EBP β的生物学功能还没有得到很好的理解，抑制细胞衰老。Cebpg（-/-）小鼠胚胎成纤维细胞（MEFs）增殖不良，过早进入衰老，并表达促炎基因特征，包括衰老相关分泌表型（SASP）基因水平升高，其致癌应激诱导需要C/EBP β。C/EBP γ的衰老抑制活性需要其与C/EBP β异二聚化的能力。C/EBP β同源二聚体（β类似于β）抑制Ras（V12）转化的NIH 3 T3细胞的增殖和致瘤性，激活SASP基因表达，并以Ras依赖性方式募集CBP共激活因子，而γ类似于β异源二聚体缺乏这些能力，并有效地挽救了Cebpg（-/-）MEFs的增殖。C/EBP β耗竭部分恢复了C/EBP γ缺陷细胞的生长，表明Cebpg（-/-）MEFs中C/EBP β同型二聚体水平的增加抑制了增殖。C/EBP γ的增殖功能不限于成纤维细胞，因为来自Cebpg（-/-）骨髓的造血祖细胞也显示出受损的生长。此外，高CEBPG表达与几种人类癌症中较差的临床预后相关，并且C/EBP γ耗竭降低肺肿瘤细胞的增殖并诱导衰老。我们的研究结果表明，C/EBP γ通过异源二聚化中和C/EBP β的细胞抑制活性，从而防止衰老并抑制SASP基因的基础转录。
C/EBP beta is an important regulator of oncogene-induced senescence (OIS). Here, we show that C/EBP gamma, a heterodimeric partner of C/EBP beta 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/EBP beta. The senescence-suppressing activity of C/EBP gamma required its ability to heterodimerize with C/EBP beta. Covalently linked C/EBP beta homodimers (beta similar to 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 similar to beta heterodimers lacked these capabilities and efficiently rescued proliferation of Cebpg(-/-) MEFs. C/EBP beta depletion partially restored growth of C/EBP gamma-deficient cells, indicating that the increased levels of C/EBP beta homodimers in Cebpg(-/-) MEFs inhibit proliferation. The proliferative functions of C/EBP gamma 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/EBP gamma depletion decreased proliferation and induced senescence in lung tumor cells. Our findings demonstrate that C/EBP gamma neutralizes the cytostatic activity of C/EBP beta through heterodimerization, which prevents senescence and suppresses basal transcription of SASP genes.