Ha-Ras transformation of MCF10A cells leads to repression of Singleminded-2s through NOTCH and C/EBPbeta.
Ha-Ras transformation of MCF10A cells leads to repression of Singleminded-2s through NOTCH and C/EBPbeta.
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DOI：
10.1038/onc.2008.497
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发表时间：
2009-03-26
期刊：
影响因子：
8
通讯作者：
Porter, W. W.
中科院分区：
文献类型：
--
作者：
Gustafson, T. L.;Wellberg, E.;Laffin, B.;Schilling, L.;Metz, R. P.;Zahnow, C. A.;Porter, W. W.
我们以前已经表明，Singleminded-2s（SIM 2s），一个基本的螺旋-环-螺旋Per-Arnt-Sim（bHLH/PAS）转录因子家族的成员，在乳腺癌样本中下调，并具有肿瘤抑制活性。然而，SIM 2s在乳腺癌细胞中被抑制的机制尚未确定。在本研究中，我们发现Harvey-Ras（Ha-Ras）转化MCF 10A细胞诱导CCAAT/增强结合蛋白β（C/EBPβ）并激活NOTCH信号通路以阻断SIM 2s基因表达。NOTCH介导的抑制作用通过C-重复结合因子1（CBF 1）-独立的机制，CBF 1的引入对SIM 2的表达没有影响。与C/ebpβ依赖性抑制SIM 2s一致，C/ebpβ−/−小鼠乳腺表达高水平的SIM 2s，并且C/ebpβ亚型的重建降低了C/ebpβ永生化乳腺上皮细胞系中的SIM 2s mRNA水平。这些研究阐明了Ha-Ras转化的乳腺上皮细胞中肿瘤抑制基因沉默的新途径，并将SIM 2鉴定为C/EBPβ和NOTCH信号传导的靶标。
We have previously shown that Singleminded-2s (SIM2s), a member of the basic helix-loop-helix Per-Arnt-Sim (bHLH/PAS) family of transcription factors, is downregulated in breast cancer samples and has tumor suppressor activity. However, the mechanism by which SIM2s is repressed in breast cancer cells has not been determined. In this study, we show that transformation of MCF10A cells by Harvey-Ras (Ha-Ras) induces CCAAT/enhance binding protein β (C/EBPβ) and activates the NOTCH signaling pathway to block SIM2s gene expression. NOTCH-mediated repression acts through a C-repeat binding factor 1 (CBF1)-independent mechanism, as introduction of CBF1 had no effect on SIM2s expression. Consistent with C/ebpβ-dependent inhibition of SIM2s, C/ebpβ−/−mouse mammary glands express high levels of SIM2s and reestablishment of C/ebpβ isoforms decreased SIM2s mRNA levels in C/ebpβ immortalized mammary epithelial cell lines. These studies illustrate a novel pathway of tumor suppressor gene silencing in Ha-Ras-transformed breast epithelial cells and identify SIM2s as a target of C/EBPβ and NOTCH signaling.
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