小柯机器人

美国斯坦福大学Julien Sage研究团队发现，AMBRA1 E3连接酶衔接蛋白调节细胞周期蛋白D的稳定性。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。

研究人员表示，细胞分裂的启动整合了大量的细胞内和细胞外输入。D型细胞周期蛋白（以下简称为细胞周期蛋白D）将这些输入与DNA复制的启动结合在一起。细胞周期蛋白D水平的升高通过激活细胞周期蛋白依赖性激酶4和6（以下称为CDK4/6）来促进细胞分裂，进而使得视网膜母细胞瘤肿瘤抑制因子磷酸化并失活。因此，细胞周期蛋白D–CDK4/6复合物水平和活性的提高与细胞生长不受抑制和癌症的发生密切相关。然而，调节细胞周期蛋白D水平的机制尚不完全清楚。

研究人员发现，自噬和Beclin 1调节因子1（AMBRA1）是细胞周期蛋白D降解的主要调节蛋白。研究人员在全基因组筛选中鉴定了AMBRA1，并研究了对CDK4/6抑制反应的遗传基础。AMBRA1的缺失会导致细胞和小鼠中细胞周期蛋白D的水平升高，从而促进增殖并降低对CDK4/6抑制的敏感性。从机理上讲，AMBRA1介导细胞周期蛋白D泛素化和蛋白酶体降解，这是作为cullin 4 E3连接酶复合物的底物受体。AMBRA1的缺失促进了小鼠模型中肺腺癌的生长，而AMBRA1的低水平与肺腺癌患者的生存期较差有关。因此，AMBRA1调节细胞周期蛋白D的细胞水平，并有助于癌症的发展和癌细胞对CDK4/6抑制剂的反应。 

附：英文原文

Title: The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D

Author: Andrea C. Chaikovsky, Chuan Li, Edwin E. Jeng, Samuel Loebell, Myung Chang Lee, Christopher W. Murray, Ran Cheng, Janos Demeter, Danielle L. Swaney, Si-Han Chen, Billy W. Newton, Jeffrey R. Johnson, Alexandros P. Drainas, Yan Ting Shue, Jose A. Seoane, Preethi Srinivasan, Andy He, Akihiro Yoshida, Susan Q. Hipkins, Edel McCrea, Carson D. Poltorack, Nevan J. Krogan, J. Alan Diehl, Christina Kong, Peter K. Jackson, Christina Curtis, Dmitri A. Petrov, Michael C. Bassik, Monte M. Winslow, Julien Sage

Issue&Volume: 2021-04-14

Abstract: The initiation of cell division integrates a large number of intra- and extracellular inputs. D-type cyclins (hereafter, cyclin D) couple these inputs to the initiation of DNA replication1. Increased levels of cyclin D promote cell division by activating cyclin-dependent kinases 4 and 6 (hereafter, CDK4/6), which in turn phosphorylate and inactivate the retinoblastoma tumour suppressor. Accordingly, increased levels and activity of cyclin D–CDK4/6 complexes are strongly linked to unchecked cell proliferation and cancer2,3. However, the mechanisms that regulate levels of cyclin D are incompletely understood4,5. Here we show that autophagy and beclin 1 regulator 1 (AMBRA1) is the main regulator of the degradation of cyclin D. We identified AMBRA1 in a genome-wide screen to investigate the genetic basis of  the response to CDK4/6 inhibition. Loss of AMBRA1 results in high levels of cyclin D in cells and in mice, which promotes proliferation and decreases sensitivity to CDK4/6 inhibition. Mechanistically, AMBRA1 mediates ubiquitylation and proteasomal degradation of cyclin D as a substrate receptor for the cullin 4 E3 ligase complex. Loss of AMBRA1 enhances the growth of lung adenocarcinoma in a mouse model, and low levels of AMBRA1 correlate with worse survival in patients with lung adenocarcinoma. Thus, AMBRA1 regulates cellular levels of cyclin D, and contributes to cancer development and the response of cancer cells to CDK4/6 inhibitors.

DOI: 10.1038/s41586-021-03474-7

Source: https://www.nature.com/articles/s41586-021-03474-7

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