Author
Listed:
- Andrea C. Chaikovsky
(Stanford University
Stanford University)
- Chuan Li
(Stanford University)
- Edwin E. Jeng
(Stanford University)
- Samuel Loebell
(Stanford University
Stanford University)
- Myung Chang Lee
(Stanford University
Stanford University)
- Christopher W. Murray
(Stanford University
Stanford University)
- Ran Cheng
(Stanford University)
- Janos Demeter
(Stanford University)
- Danielle L. Swaney
(University of California, San Francisco
University of California, San Francisco
Gladstone Insitutes)
- Si-Han Chen
(University of California, San Francisco
University of California, San Francisco
Gladstone Insitutes)
- Billy W. Newton
(University of California, San Francisco
University of California, San Francisco
Gladstone Insitutes)
- Jeffrey R. Johnson
(University of California, San Francisco
University of California, San Francisco
Gladstone Insitutes)
- Alexandros P. Drainas
(Stanford University
Stanford University)
- Yan Ting Shue
(Stanford University
Stanford University)
- Jose A. Seoane
(Stanford University
Stanford University)
- Preethi Srinivasan
(Stanford University
Stanford University)
- Andy He
(Stanford University
Stanford University)
- Akihiro Yoshida
(Case Western Reserve University
School of Medicine, Case Western Reserve University)
- Susan Q. Hipkins
(Stanford University
Stanford University)
- Edel McCrea
(Stanford University
Stanford University)
- Carson D. Poltorack
(Stanford University
Stanford University)
- Nevan J. Krogan
(University of California, San Francisco
University of California, San Francisco
Gladstone Insitutes)
- J. Alan Diehl
(Case Western Reserve University
School of Medicine, Case Western Reserve University)
- Christina Kong
(Stanford University)
- Peter K. Jackson
(Stanford University)
- Christina Curtis
(Stanford University
Stanford University)
- Dmitri A. Petrov
(Stanford University)
- Michael C. Bassik
(Stanford University)
- Monte M. Winslow
(Stanford University
Stanford University)
- Julien Sage
(Stanford University
Stanford University)
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.
Suggested Citation
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., 2021.
"The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D,"
Nature, Nature, vol. 592(7856), pages 794-798, April.
Handle:
RePEc:nat:nature:v:592:y:2021:i:7856:d:10.1038_s41586-021-03474-7
DOI: 10.1038/s41586-021-03474-7
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Cited by:
- Shizhong Ke & Fabin Dang & Lin Wang & Jia-Yun Chen & Mandar T. Naik & Wenxue Li & Abhishek Thavamani & Nami Kim & Nandita M. Naik & Huaxiu Sui & Wei Tang & Chenxi Qiu & Kazuhiro Koikawa & Felipe Batal, 2024.
"Reciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry,"
Nature Communications, Nature, vol. 15(1), pages 1-21, December.
- Ming Liu & Yang Wang & Fei Teng & Xinyi Mai & Xi Wang & Ming-Yuan Su & Goran Stjepanovic, 2023.
"Structure of the DDB1-AMBRA1 E3 ligase receptor complex linked to cell cycle regulation,"
Nature Communications, Nature, vol. 14(1), pages 1-12, December.
- Bonnie Huang & James D. Phelan & Silvia Preite & Julio Gomez-Rodriguez & Kristoffer H. Johansen & Hirofumi Shibata & Arthur L. Shaffer & Qin Xu & Brendan Jeffrey & Martha Kirby & Stacie Anderson & Yan, 2022.
"In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells,"
Nature Communications, Nature, vol. 13(1), pages 1-16, December.
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