2月19日最新出版的Cell雜志刊發(fā)了一篇Merlin/NF2抑制腫瘤發(fā)生的機(jī)制研究論文,，這一新成果成為新一期Cell的封面文章，主要解析了Merlin/NF2通過(guò)抑制E3泛素化連接酶從而抑制腫瘤發(fā)生的機(jī)制,。
早前的生物模型研究發(fā)現(xiàn),，腫瘤抑制基因NF2編碼一個(gè)含有FERM區(qū)域的蛋白Merlin，Merlin蛋白具有在細(xì)胞外胞漿附近抑制絲裂信號(hào)的功能,。
在本研究中,，科學(xué)家們發(fā)現(xiàn)，閉合型的Merlin蛋白（已經(jīng)停止生長(zhǎng)）聚集在細(xì)胞核內(nèi),，并且能與E3泛素化鏈接酶CRL4DCAF1結(jié)合,，并且抑制E3泛素化鏈接酶CRL4DCAF1的生物活性。
研究發(fā)現(xiàn)缺失DCAF1能阻斷Merlin抑制絲裂信號(hào)的功能,。相反,，增強(qiáng)對(duì)Merlin不敏感的突變型DCAF1的表達(dá)量也可中和Merlin抑制絲裂信號(hào)的作用。再度表達(dá)Merlin與沉默DCAF1可產(chǎn)生類(lèi)似抗腫瘤的作用,，通過(guò)基因的表達(dá)來(lái)抑制腫瘤的發(fā)生,。癌變衍生的變異常常導(dǎo)致Merlin功能失效。
研究者們通過(guò)一系列實(shí)驗(yàn)發(fā)現(xiàn),，Merlin蛋白具有抑制腫瘤發(fā)生的功能,，它主要通過(guò)抑制細(xì)胞核中的CRL4 DCAF1來(lái)發(fā)揮抑癌作用。（生物谷Bioon.com）
生物谷推薦原始出處：
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
