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Cell:Merlin/NF2通过抑制E3泛素化连接酶防治肿瘤

来源:网络 2010-02-24 09:28

专题:Cell专题

2月19日最新出版的Cell杂志刊发了一篇Merlin/NF2抑制肿瘤发生的机制研究论文,这一新成果成为新一期Cell的封面文章,主要解析了Merlin/NF2通过抑制E3泛素化连接酶从而抑制肿瘤发生的机制。

早前的生物模型研究发现,肿瘤抑制基因NF2编码一个含有FERM区域的蛋白Merlin,Merlin蛋白具有在细胞外胞浆附近抑制丝裂信号的功能。

在本研究中,科学家们发现,闭合型的Merlin蛋白(已经停止生长)聚集在细胞核内,并且能与E3泛素化链接酶CRL4DCAF1结合,并且抑制E3泛素化链接酶CRL4DCAF1的生物活性。

研究发现缺失DCAF1能阻断Merlin抑制丝裂信号的功能。相反,增强对Merlin不敏感的突变型DCAF1的表达量也可中和Merlin抑制丝裂信号的作用。再度表达Merlin与沉默DCAF1可产生类似抗肿瘤的作用,通过基因的表达来抑制肿瘤的发生。癌变衍生的变异常常导致Merlin功能失效。

研究者们通过一系列实验发现,Merlin蛋白具有抑制肿瘤发生的功能,它主要通过抑制细胞核中的CRL4  DCAF1来发挥抑癌作用。(生物谷Bioon.com)

生物谷推荐原始出处:

Cell, Volume 140, Issue 4, 477-490, 19 February 2010 DOI:10.1016/j.cell.2010.01.029

Merlin/NF2 Suppresses Tumorigenesis by Inhibiting the E3 Ubiquitin Ligase CRL4DCAF1 in the Nucleus

Wei Li, Liru You, Jonathan Cooper, Gaia Schiavon, Angela Pepe-Caprio, Lu Zhou, Ryohei Ishii, Marco Giovannini, C. Oliver Hanemann, Stephen B. Long, Hediye Erdjument-Bromage, Pengbo Zhou, Paul Tempst, Filippo G. Giancotti
 
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA Sloan-Kettering Division, Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA Peninsula College of Medicine and Dentistry, University of Plymouth, Plymouth PL6 8BU, UK Department of Pathology and Laboratory Medicine, Weil Cornell Medical College, New York, NY 10065, USA House Ear Institute, Center for Neural Tumor Research, Los Angeles, CA 90057, USA

Current models imply that the FERM domain protein Merlin, encoded by the tumor suppressor NF2, inhibits mitogenic signaling at or near the plasma membrane. Here, we show that the closed, growth-inhibitory form of Merlin accumulates in the nucleus, binds to the E3 ubiquitin ligase CRL4DCAF1, and suppresses its activity. Depletion of DCAF1 blocks the promitogenic effect of inactivation of Merlin. Conversely, enforced expression of a Merlin-insensitive mutant of DCAF1 counteracts the antimitogenic effect of Merlin. Re-expression of Merlin and silencing of DCAF1 implement a similar, tumor-suppressive program of gene expression. Tumor-derived mutations invariably disrupt Merlin's ability to interact with or inhibit CRL4DCAF1. Finally, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. We propose that Merlin suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4DCAF1.

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