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研究发现CRL4 AMBRA1是D型细胞周期蛋白的主调节因子
2021-04-16 15:10

美国纽约大学格罗斯曼医学院Michele Pagano和宾夕法尼亚大学佩雷尔曼医学院Luca Busino团队合作发现,CRL4 AMBRA1是D型细胞周期蛋白的主调节因子。这一研究成果于2021年4月14日在线发表在国际学术期刊《自然》上。

通过结合体细胞的生化和遗传学研究,研究人员发现CRL4 AMBRA1(也称为CRL4DCAF3)是修饰所有三个D型细胞周期蛋白降解的泛素连接酶。在发育过程中,Ambra1的缺失会诱导D型细胞周期蛋白和视网膜母细胞瘤(RB)过度磷酸化和过度积累,并导致神经系统缺陷,这种缺陷可以通过使用FDA批准的CDK4和CDK6(CDK4/6 )抑制剂abemaciclib来缓解。

此外,AMBRA1在小鼠模型中起着抑癌作用,而低水平AMBRA1 mRNA则预示癌症患者的不良愈后。D型细胞周期蛋白中的癌症热点突变解除了它们与AMBRA1的结合并诱导了其稳定。最后,通过全基因组CRISPR–Cas9筛选,研究确定AMBRA1是CDK4/6抑制反应的调节因子。AMBRA1的缺失通过促进D型细胞周期蛋白与CDK2复合物的形成而降低了对CDK4/6抑制剂的敏感性。

总的来说,该研究结果揭示了控制D型细胞周期蛋白在细胞周期进程、发育中和人类癌症中稳定性的分子机制,并暗示AMBRA1是RB途径的关键调节因子。

据介绍,D型细胞周期蛋白是细胞分裂周期的主要调节因子,是人类癌症中最常出现的发生错误调控的靶点之一,但调节其更新的机制仍亟待阐明。

附:英文原文

Title: CRL4 AMBRA1 is a master regulator of D-type cyclins

Author: Daniele Simoneschi, Gergely Rona, Nan Zhou, Yeon-Tae Jeong, Shaowen Jiang, Giacomo Milletti, Arnaldo A. Arbini, Alfie OSullivan, Andrew A. Wang, Sorasicha Nithikasem, Sarah Keegan, Yik Siu, Valentina Cianfanelli, Emiliano Maiani, Francesca Nazio, Francesco Cecconi, Francesco Boccalatte, David Feny, Drew R. Jones, Luca Busino, Michele Pagano

Issue&Volume: 2021-04-14

Abstract: D-type cyclins are central regulators of the cell division cycle and are among the most frequently deregulated therapeutic targets in human cancer1, but the mechanisms that regulate their turnover are still being debated2,3. Here, by combining biochemical and genetics studies in somatic cells, we identify CRL4AMBRA1 (also known as CRL4DCAF3) as the ubiquitin ligase that targets all three D-type cyclins for degradation. During development, loss of Ambra1 induces the accumulation of D-type cyclins and retinoblastoma (RB) hyperphosphorylation and hyperproliferation, and results in defects of the nervous system that are reduced by treating pregnant mice with the FDA-approved CDK4 and CDK6 (CDK4/6) inhibitor abemaciclib. Moreover, AMBRA1 acts as a tumour suppressor in mouse models and low AMBRA1 mRNA levels are predictive of poor survival in cancer patients. Cancer hotspot mutations in D-type cyclins abrogate their binding to AMBRA1 and induce their stabilization. Finally, a whole-genome, CRISPR–Cas9 screen identified AMBRA1 as a regulator of the response to CDK4/6 inhibition. Loss of AMBRA1 reduces sensitivity to CDK4/6 inhibitors by promoting the formation of complexes of D-type cyclins with CDK2. Collectively, our results reveal the molecular mechanism that controls the stability of D-type cyclins during cell-cycle progression, in development and in human cancer, and implicate AMBRA1 as a critical regulator of the RB pathway.

DOI: 10.1038/s41586-021-03445-y

Source: https://www.nature.com/articles/s41586-021-03445-y

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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