4-hydroxynonenal inhibits telomerase activity and hTERT expression in human leukemic cell lines
4-hydroxynonenal inhibits telomerase activity and hTERT expression in human leukemic cell lines
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DOI：
10.1016/j.freeradbiomed.2005.12.024
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发表时间：
2006-05-01
影响因子：
7.4
通讯作者：
Barrera, Giuseppina
中科院分区：
文献类型：
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作者：
Pizzimenti, Stefania;Briatore, Federica;Barrera, Giuseppina
氧化应激过程中产生的4-羟基壬烯醛（HNE）在几种肿瘤细胞中具有抗增殖/分化作用。最近，已经观察到氧化应激加速端粒的损失。端粒的长度取决于端粒酶的活性，而端粒酶的催化亚基（hTERT）在大多数人类癌症中被强烈上调，并被分化剂抑制。本文报道了HNE对三种人白血病细胞系HL-60、U937、ML-1端粒酶活性和hTERT表达的抑制作用。为了探讨HNE下调hTERT的分子机制，我们还研究了几种转录因子的表达：在所有这些细胞系中，c-Myc被抑制，Mad-1被上调，Sp-1不受影响。此外，在p53野生型ML-1细胞中，HNE上调p53的表达。在HL-60细胞中，c-Myc和Mad-1与hTERT启动子E-box序列的DNA结合活性分别被抑制和上调。综上所述，HNE通过调节c-Myc/Mad-1转录因子表达，降低hTERT启动子活性，从而抑制端粒酶活性。(c) 2005爱思唯尔公司版权所有。
4-Hydroxynonenal (HNE), produced during oxidative stress, has an antiproliferative/differentiative effect in several tumor cells. Recently, it has been observed that oxidative stress accelerates telomere loss. The length of telomeres depends on the telomerase activity, and the catalytic subunit of telomerase (hTERT) is strongly up-regulated in most human cancers and inhibited by differentiating agents. In this paper the inhibitory effect of HNE on telomerase activity and hTERT expression in three human leukemic cell lines (HL-60, U937, ML-1) is reported. To investigate the molecular mechanism involved in hTERT down-regulation by HNE, the expression of several transcription factors was also studied: in all these cell lines, c-Myc was inhibited, Mad-1 was up-regulated, and Sp-1 was not affected. Moreover, in p53 wild-type ML-1 cells, HNE up-regulated p53 expression. In HL-60 cells, DNA binding activity of c-Myc and Mad-1 to the E-box sequence of the hTERT promoter was inhibited and up-regulated, respectively. In summary, HNE inhibits telomerase activity via decreased hTERT promoter activity, by modulating c-Myc/Mad-1 transcription factor expression. (c) 2005 Elsevier Inc. All rights reserved.