Bone morphogenetic protein-7 induces telomerase inhibition, telomere shortening, breast cancer cell senescence, and death via Smad3 (Retracted article. See vol 23, pg 2790, 2009)
Bone morphogenetic protein-7 induces telomerase inhibition, telomere shortening, breast cancer cell senescence, and death via Smad3 (Retracted article. See vol 23, pg 2790, 2009)
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DOI：
10.1096/fj.08-119529
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发表时间：
2009-06-01
期刊：
影响因子：
4.8
通讯作者：
Liu, Jun-Ping
中科院分区：
文献类型：
--
作者：
Cassar, Lucy;Nicholls, Craig;Liu, Jun-Ping
人端粒酶逆转录酶（Human telomerase reverse transcriptase，hTERT）是维持细胞端粒的关键酶，但细胞外信号如何调控端粒的维持尚不清楚。在这里，我们报告细胞因子骨形态发生蛋白-7（BMP 7）诱导Smad 3磷酸化，核转位和hTERT基因抑制。BMP 7以时间和浓度依赖性方式诱导乳腺癌细胞中Smad 3依赖性端粒酶抑制乳腺癌细胞长期暴露于BMP 7导致端粒缩短、细胞衰老和凋亡。BMPRII受体的突变，而不是TGF β RII、ACTRIIA或ACTRIIB，阻断了BMP 7诱导的hTERT基因启动子活性的抑制，导致端粒酶活性增加、端粒延长和细胞持续增殖。hTERT表达抑制BMP 7诱导的乳腺癌细胞衰老和凋亡因此，我们的数据表明，BMP 7诱导乳腺癌细胞衰老和死亡的机制，涉及抑制端粒酶活性和端粒的维护通过BMPRII受体和Smad 3介导的抑制hTERT基因。卡萨湖尼科尔斯角，平托，A. R.，Li，H.，刘杰-骨形态发生蛋白-7通过Smad 3诱导端粒酶抑制、端粒缩短、乳腺癌细胞衰老和死亡。FASEB J. 23，1880-1892（2009）
Human telomerase reverse transcriptase (hTERT) is central to maintain telomeres for continuous cell proliferation, but it remains unknown how extracellular cues regulate telomerase maintenance of telomeres. Here we report that the cytokine bone morphogenetic protein-7 (BMP7) induces Smad3 phosphorylation, nuclear translocation, and hTERT gene repression. BMP7 induces Smad3-dependent telomerase inhibition in a time- and concentration-dependent manner in breast cancer cells. Chronic exposure of breast cancer cells to BMP7 results in short telomeres, cell senescence, and apoptosis. Mutation of BMPRII receptor, but not TGF beta RII, ACTRIIA, or ACTRIIB, blocked BMP7-induced repression of the hTERT gene promoter activity, leading to increased telomerase activity, lengthened telomeres, and continued cell proliferation. Expression of hTERT inhibits BMP7-induced breast cancer cell senescence and apoptosis. Thus, our data suggest that BMP7 induces breast cancer cell aging and death by a mechanism involving inhibition of telomerase activity and telomere maintenance via BMPRII receptor- and Smad3-mediated repression of the hTERT gene.-Cassar, L., Nicholls, C., Pinto, A. R., Li, H., Liu, J.-P. Bone morphogenetic protein-7 induces telomerase inhibition, telomere shortening, breast cancer cell senescence, and death via Smad3. FASEB J. 23, 1880-1892 (2009)