多种瘤抑制途径负面调节端粒酶
Shiaw Yih Lin1, Stephen J Elledge
1Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Cell
|July 3, 2003
概括
端粒酶 (hTERT) 在大多数细胞中被抑制,但在癌症中活跃. 这项研究确定了调节hTERT的三个瘤抑制途径 (Mad1/c-Myc,SIP1和Menin),揭示了癌症发展的洞察力.
科学领域:
- 分子生物学分子生物学
- 癌症研究 癌症研究
- 遗传学 是一个遗传学.
背景情况:
- 端粒酶表达通常在体细胞中被抑制,但在干细胞和许多人类癌症中活跃.
- 假设端粒酶活性对瘤发生和维持干细胞特性至关重要.
- 了解端粒酶调节是开发癌症治疗的关键.
研究的目的:
- 为了确定人类端粒酶逆转录酶 (hTERT) 表达的负调节剂.
- 阐明瘤抑制剂和瘤基因通路在控制端粒酶活性中的作用.
主要方法:
- 利用通用基因选来识别hTERT的负调节者.
- 研究了与hTERT抑制有关的Mad1/c-Myc,TGF-β/SIP1和Menin通路.
- 评估了Menin枯竭对人类初级纤维细胞和转化表型的影响.
主要成果:
- 确定了三种不同的瘤抑制剂/瘤基因途径参与hTERT抑制:Mad1/c-Myc,SIP1 (TGF-β标) 和Menin.
- 证实了Mad1/c-Myc通路在hTERT调节中的作用.
- 证明SIP1调解了TGF-β调节的hTERT抑制.
- 显示Menin直接抑制hTERT,其耗尽使纤维细胞永生,并促进转化.
结论:
- 多个瘤抑制和瘤基因通路协调抑制hTERT表达.
- 在人类瘤中,端粒酶的重新激活可能是通过破坏这些调节通路的瘤基因突变发生的.
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