通过抑制mTOR,PML可以抑制HIF-1α翻译和新血管生成
Rosa Bernardi1, Ilhem Guernah, David Jin
1Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Avenue, New York, New York 10021, USA.
Nature
|August 18, 2006
概括
孕细胞白血病 (PML) 蛋白质通过调节蛋白质合成来抑制新的血管形成 (新血管生成). 失去PML会增强瘤生长和血管发育,提供新的治疗点.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 质白血病 (PML) 瘤抑制剂的丧失与各种人类癌症有关.
- 已知PML的功能包括诱导生长停止,细胞衰老和亡.
研究的目的:
- 在缺血和瘤条件下调查PML在新血管生成中的作用.
- 阐明PML调节新血管形成的分子机制.
主要方法:
- 研究了PML对蛋白质翻译的影响,特别是缺氧诱导因子1alpha (HIF-1alpha) 合成.
- 检查了PML,哺乳动物目标拉巴素 (mTOR) 和Rheb.之间的相互作用.
- 评估了PML-/-细胞和瘤对拉帕米辛治疗的敏感性.
- 在小鼠和人类样本中分析了核糖体蛋白S6酸化和瘤血管生成.
主要成果:
- 在体内,PML作为新血管生成的关键抑制剂.
- 在低氧条件下,PML抑制了mTOR活性,从而控制了HIF-1α合成.
- PML在物理上与mTOR相互作用,促进其核积累,并对其与Rheb.的关联进行负面调节.
- Pml-/-细胞和瘤对拉巴胺素的敏感性增加,血管新生和核糖体蛋白S6酸化增加.
结论:
- PML被确定为一种新的mTOR信号和新血管生成抑制剂.
- 这些发现凸显了PML在控制瘤血管化和生长方面的关键作用.
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