Cell：沪交大医学院找到阻断肿瘤血管生长途径
程金科博士和他所领导的科研团队，在肿瘤细胞生成研究领域获得一项重要发现。这一发现被认为有可能为抑制实体肿瘤的生成与生长找到一个新的作用“靶点”，并为肿瘤的早期发现提供一个特异性的新“指标”。
上海交通大学医学院医学科学研究院程金科博士关于(SENP1)调控缺氧诱导因子1功能方面的研究成果，刊载今天正式出版的世界顶尖生物学期刊《细胞》上。国际医学科学界对这一发现在肿瘤诊断与治疗方面所具有的“潜在应用前景”，表示出了极大的关注。
以往的研究已经证实，肿瘤的生长会伴随“缺氧”情况，因此而加速分泌的“血管内皮生长因子”，此时会发出“救助”信号，周围血管于是向肿瘤方向集中生成，进而使获得了大量养分的肿瘤细胞得以继续有恃无恐地疯长。而“血管内皮生长因子”的活动，则受一种叫做“缺氧诱导因子1”的物质的调节与控制。
“我们研究的意义，就是发现了‘缺氧诱导因子1’受‘类泛素蛋白酶1’的调控”。程金科博士解释说，类泛素蛋白酶1是促进肿瘤生成的一个重要分子。科研人员采用“基因敲除”的策略，建立了类泛素蛋白酶1的“基因敲除老鼠”。在对这个被人为造成基因突变的“贫血老鼠”的表象观察中，他们发现了在缺氧条件下，类泛素蛋白酶1调节缺氧诱导因子1稳定与活性的分子机制。“这也许是我们最终能够找到‘阻断’肿瘤血管生长的一条崭新途径！”
作为领军人才从美国M. D. Anderson癌症中心引进回国的程金科博士，目前担任上海交大医学院医学科学研究院细胞信号传导研究室主任。这项成果是M. D. Anderson癌症中心与上海交通大学医学院合作的结果。
原始出处:
Cell, Vol 131, 584-595, 02 November 2007
Article
SUMO-Specific Protease 1 Is Essential for Stabilization of HIF1α during Hypoxia
Jinke Cheng,1,3 Xunlei Kang,2,3 Sui Zhang,1 and Edward T.H. Yeh1,2,
1 Department of Cardiology, the University of Texas M.D. Anderson Cancer Center, The University of Texas, Houston Health Science Center, Houston, TX 77030, USA
2 Center for Cardiovascular Research, Brown Foundation Institute of Molecular Medicine, The University of Texas, Houston Health Science Center, Houston, TX 77030, USA
3 Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, P. R. China
Corresponding author
Edward T.H. Yeh
etyeh@mdanderson.org
SUMOylation is a dynamic process, catalyzed by SUMO-specific ligases and reversed by Sentrin/SUMO-specific proteases (SENPs). The physiologic consequences of SUMOylation and deSUMOylation are not fully understood. Here we investigate the phenotypes of mice lacking SENP1 and find that SENP1−/− embryos show severe fetal anemia stemming from deficient erythropoietin (Epo) production and die midgestation. We determine that SENP1 controls Epo production by regulating the stability of hypoxia-inducible factor 1α (HIF1α) during hypoxia. Hypoxia induces SUMOylation of HIF1α, which promotes its binding to a ubiquitin ligase, von Hippel-Lindau (VHL) protein, through a proline hydroxylation-independent mechanism, leading to its ubiquitination and degradation. In SENP1−/− MEFs, hypoxia-induced transcription of HIF1α-dependent genes such as vascular endothelial growth factor (VEGF) and glucose transporter 1 (Glut-1) is markedly reduced. These results show that SENP1 plays a key role in the regulation of the hypoxic response through regulation of HIF1α stability and that SUMOylation can serve as a direct signal for ubiquitin-dependent degradation.
相关报道:
- 众说风云 (已有0条评论)
