Transforming growth factor-β inhibits telomerase through SMAD3 and E2F transcription factors
Transforming growth factor-β inhibits telomerase through SMAD3 and E2F transcription factors
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DOI：
10.1016/j.cellsig.2007.08.012
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发表时间：
2008-01-01
影响因子：
4.8
通讯作者：
Lebrun, Jean-Jacques
中科院分区：
文献类型：
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作者：
Lacerte, Annie;Korah, Juliana;Lebrun, Jean-Jacques
癌症是由细胞内的多种基因变化引起的，其中结构性端粒酶活性和获得永生是关键。端粒酶的蛋白质成分hTERT在大多数癌细胞中的表达增加。转化生长因子-β(TGF-β)是一种有效的肿瘤抑制因子，已有报道可调节hTERT的表达。我们发现，转化生长因子β抑制正常细胞和癌细胞中hTERT的表达，这种作用是通过SMAD3介导的，但也需要ERK1/2、p38激酶和历史脱乙酰酶活性。此外，我们在hTERT基因启动子内确定了四个关键的E2F转录因子结合位点，它们提供了转化生长因子β反应。最后，利用E2F-1基因敲除模型，我们发现E2F-1的缺失可以取消转化生长因子β对端粒酶表达的抑制。这些发现突出了转化生长因子β在调节端粒酶表达方面的突出作用，并确定SMAD3和E2F-1是转化生长因子β在正常细胞和癌细胞中作用的关键介质。(C)2007 Elsevier Inc.保留所有权利。
Cancer arises from multiple genetic changes within the cell, among which constitutive telomerase activity and attainment of immortality are central. Expression of hTERT, the protein component of telomerase, is increased in most cancer cells. Transforming growth factor-beta (TGF beta), a potent tumor suppressor, has been reported to regulate hTERTexpression. We found that TGF beta represses hTERTexpression in normal and cancer cells and that this effect is mediated through Smad3 but also requires Erk1/2, p38 kinase and historic deacetylase activity. Furthermore, we identified four critical E2F transcription factor binding sites within the hTERT gene promoter that confer the TGF beta response. Finally, using the E2F-1 knockout model, we showed that loss of E2F-1 abolishes TGF beta inhibition of telomerase expression. These findings highlight the prominent role of TGF beta in regulating telomerase expression and identify Smad3 and E2F-1 as critical mediators of TGF beta effects in both normal and cancer cells. (C) 2007 Elsevier Inc. All rights reserved.