梅林肿瘤抑制作用与抑制 E3 泛素连接酶 CRL4（DCAF1）有关。
Merlin's tumor suppression linked to inhibition of the E3 ubiquitin ligase CRL4 (DCAF1).
机构信息
Sloan-Kettering Institute for Cancer Research, New York, NY, USA.
出版信息
Cell Cycle. 2010 Nov 15;9(22):4433-6. doi: 10.4161/cc.9.22.13838.
Abstract
The mechanism by which the FERM domain protein Merlin, encoded by the tumor suppressor NF2, restrains cell proliferation is poorly understood. Prior studies have suggested that Merlin exerts its antimitogenic effect by interacting with multiple signaling proteins located at or close to the plasma membrane. We have recently observed that Merlin translocates into the nucleus and binds to and inhibits the E3 ubiquitin ligase CRL4 (DCAF1) . Genetic evidence indicates that inactivation of Merlin induces oncogenic gene expression, hyperproliferation, and tumorigenicity by unleashing the activity of CRL4 (DCAF1) . In addition to providing a potential explanation for the diverse effects that loss of Merlin exerts in multiple cell types, these findings suggest that compounds inhibiting CRL4 (DCAF1) may display therapeutic efficacy in Neurofibromatosis type 2 and other cancers driven by Merlin inactivation.
摘要
神经纤维瘤病 2 型（NF2）抑癌基因编码的 FERM 域蛋白 Merlin 抑制细胞增殖的机制尚不清楚。先前的研究表明 Merlin 通过与位于质膜或接近质膜的多种信号蛋白相互作用发挥其抗有丝分裂作用。我们最近观察到 Merlin 易位到细胞核，并与 E3 泛素连接酶 CRL4（DCAF1）结合并抑制其活性。遗传证据表明， Merlin 的失活通过释放 CRL4（DCAF1）的活性诱导致癌基因表达、过度增殖和致瘤性。除了为 Merlin 在多种细胞类型中产生的不同作用提供潜在解释外，这些发现表明抑制 CRL4（DCAF1）的化合物可能在由 Merlin 失活驱动的神经纤维瘤病 2 型和其他癌症中显示出治疗效果。
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