The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D

• Published in: Nature (London) Vol. 592; no. 7856; pp. 794 - 798
• Main Authors: Chaikovsky, Andrea C., Li, Chuan, Jeng, Edwin E., Loebell, Samuel, Lee, Myung Chang, Murray, Christopher W., Cheng, Ran, Demeter, Janos, Swaney, Danielle L., Chen, Si-Han, Newton, Billy W., Johnson, Jeffrey R., Drainas, Alexandros P., Shue, Yan Ting, Seoane, Jose A., Srinivasan, Preethi, He, Andy, Yoshida, Akihiro, Hipkins, Susan Q., McCrea, Edel, Poltorack, Carson D., Krogan, Nevan J., Diehl, J. Alan, Kong, Christina, Jackson, Peter K., Curtis, Christina, Petrov, Dmitri A., Bassik, Michael C., Winslow, Monte M., Sage, Julien
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.04.2021; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/2; 13/31; 13/51; 13/89; 13/95; 14/63; 38; 38/109; 38/22; 38/35; 38/39; 38/70; 38/88; 38/91; 45/22; 49; 631/337/474/2073; 631/337/641; 64/60; 82; 82/58; 82/83; 96/95; Adaptor Proteins, Signal Transducing - metabolism; Adenocarcinoma; Adenocarcinoma of Lung - genetics; Animals; Autophagy; Cancer; Cell cycle; Cell Division; Cell proliferation; Cellular control mechanisms; Cullin; Cyclin D; Cyclin D - metabolism; Cyclin D proteins; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - metabolism; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - metabolism; Cyclin-dependent kinases; Degradation; Deoxyribonucleic acid; Development and progression; DNA; DNA biosynthesis; Gene expression; Genes, Tumor Suppressor; Genetic aspects; Genomes; Health aspects; Humanities and Social Sciences; Humans; Kinases; Ligases; Lung cancer; Lung Neoplasms - genetics; Lungs; Mice; multidisciplinary; Phagocytosis; Phosphorylation; Piperazines - pharmacology; Proteasomes; Proteins; Proteomics; Pyridines - pharmacology; Replication initiation; Retina; Retinoblastoma; Science; Science (multidisciplinary); Substrates; Tumor suppressor genes; Tumors; U937 Cells; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; United States
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-021-03474-7

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 replication 1 . 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 cancer 2 , 3 . However, the mechanisms that regulate levels of cyclin D are incompletely understood 4 , 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.