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"]
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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. AMBRA1 is the main regulator of the degradation of D-type cyclins, and loss of AMBRA1 promotes cell proliferation and tumour growth, and reduces the sensitivity of cancer cells to inhibition of CDK4 and CDK6.Cite this article
Chaikovsky, A.C., Li, C., Jeng, E.E. et al. The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D. Nature (2021). https://doi.org/10.1038/s41586-021-03474-7 