Sustained NF-kappaB activation produces a short-term cell proliferation block in conjunction with repressing effectors of cell cycle progression controlled by E2F or FoxM1.
Sustained NF-kappaB activation produces a short-term cell proliferation block in conjunction with repressing effectors of cell cycle progression controlled by E2F or FoxM1.
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DOI：
10.1002/jcp.21596
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发表时间：
2009-01
影响因子：
5.6
通讯作者：
Marcu, Kenneth B.
中科院分区：
文献类型：
--
作者：
Penzo, Marianna;Massa, Paul E.;Olivotto, Eleonora;Bianchi, Francesca;Borzi, Rosa Maria;Hanidu, Adedayo;Li, Xiang;Li, Jun;Marcu, Kenneth B.
NF-κB转录因子诱导许多参与促炎/应激样反应的基因;但持续NF-κB激活对其他细胞基因表达编程的附带效应和后果仍不太清楚。在这里，组成型活性IKKβ T环突变体（IKKβca）的强制表达驱使小鼠成纤维细胞进入短暂的生长停滞，在连续培养2-3周内消退。增殖停滞与G1/S期阻滞永生化和原代早期MEFs。永生化MEFs的分子分析显示，IKKβca逆转录病毒感染后最初1-2周内细胞增殖的抑制与E2 F或FoxM 1已知靶点的基本细胞周期效应子的短暂协同抑制有关。抗磷酸化IκBα超级阻遏物和IKKβca的共表达消除了生长停滞和细胞周期效应物阻遏，从而将IKKβca的作用与典型的NF-κB激活联系起来。IKKβca细胞的短暂生长停滞与p21（细胞周期蛋白依赖性激酶抑制剂1A）蛋白表达增强相关，部分原因是NF-κB的转录激活，也可能是由于Skp 2和Csk 1的强烈抑制，这两个都是FoxM 1介导蛋白酶体依赖性p21转换的直接靶点。在永生化MEFs中去除p21可减少IKKβca介导的生长抑制。此外，抑制HDACs可减轻IKKβca诱导的E2 F和FoxM 1靶基因表达的抑制，表明IKKβca中染色质介导的基因沉默对E2 F和FoxM 1靶基因表达的短期抑制作用。
NF-κB transcription factors induce a host of genes involved in pro-inflammatory/stress-like responses; but the collateral effects and consequences of sustained NF-κB activation on other cellular gene expression programming remain less well understood. Here enforced expression of a constitutively active IKKβ T-loop mutant (IKKβca) drove murine fibroblasts into transient growth arrest that subsided within 2-3 weeks of continuous culture. Proliferation arrest was associated with a G1/S phase block in immortalized and primary early passage MEFs. Molecular analysis in immortalized MEFs revealed that inhibition of cell proliferation in the initial 1-2 weeks after their IKKβca retroviral infection was linked to the transient, concerted repression of essential cell cycle effectors that are known targets of either E2F or FoxM1. Co-expression of a phosphorylation resistant IκBα super repressor and IKKβca abrogated growth arrest and cell cycle effector repression, thereby linking IKKβca's effects to canonical NF-κB activation. Transient growth arrest of IKKβca cells was associated with enhanced p21 (cyclin-dependent kinase inhibitor 1A) protein expression, due in part to transcriptional activation by NF-κB and also likely due to strong repression of Skp2 and Csk1, both of which are FoxM1 direct targets mediating proteasomal dependent p21 turnover. Ablation of p21 in immortalized MEFs reduced their IKKβca mediated growth suppression. Moreover, trichostatin A inhibition of HDACs alleviated the repression of E2F and FoxM1 targets induced by IKKβca, suggesting chromatin mediated gene silencing in IKKβca's short term repressive effects on E2F and FoxM1 target gene expression.
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