The AMBRA1 E3 ligase adaptor regulates Cyclin D protein stability
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ABSTRACT:
PROVIDER: PRJNA670881 | ENA |
REPOSITORIES: ENA
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Project description: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.
2021-02-04 | GSE146303 | GEO
Project description:The initiation of cell division is a fundamental process that integrates a large number of intra- and extra-cellular inputs. In mammalian cells, D-type cyclins (Cyclin D) couple these inputs to the decision to initiate DNA replication. Increased levels of Cyclin D promote cell cycle progression by activating cyclin-dependent kinases 4 and 6 (CDK4/6). Accordingly, increased levels and activity of Cyclin D and their associated kinases are strongly linked to unchecked cell proliferation and tumor development. Despite this central role of Cyclin D in cell cycle progression, the mechanisms regulating their levels remain incompletely understood. Here we describe AMBRA1 as the main regulator of Cyclin D protein degradation. We first identify AMBRA1 as the top candidate in a genome-wide CRISPR/Cas9 loss-of-function screen investigating the genetic basis of resistance to chemical CDK4/6 inhibition. AMBRA1 loss results in high protein levels of Cyclin D in cells and in mice. AMBRA1 loss further promotes lung cancer development in a mouse model, and low levels of AMBRA1 correlate with worse survival in lung cancer patients. Mechanistically, AMBRA1 acts as a substrate receptor for the Cullin 4 E3 ligase complex to promote ubiquitylation and proteasomal degradation of the three Cyclin D family members. Thus, AMBRA1 regulates Cyclin D protein levels and contributes to the development of cancer as well as the response of cancer cells to CDK4/6 inhibitors.
2021-02-05 | GSE159920 | GEO
Project description:The initiation of cell division is a fundamental process that integrates a large number of intra- and extra-cellular inputs. In mammalian cells, D-type cyclins (Cyclin D) couple these inputs to the decision to initiate DNA replication. Increased levels of Cyclin D promote cell cycle progression by activating cyclin-dependent kinases 4 and 6 (CDK4/6). Accordingly, increased levels and activity of Cyclin D and their associated kinases are strongly linked to unchecked cell proliferation and tumor development. Despite this central role of Cyclin D in cell cycle progression, the mechanisms regulating their levels remain incompletely understood. Here we describe AMBRA1 as the main regulator of Cyclin D protein degradation. We first identify AMBRA1 as the top candidate in a genome-wide CRISPR/Cas9 loss-of-function screen investigating the genetic basis of resistance to chemical CDK4/6 inhibition. AMBRA1 loss results in high protein levels of Cyclin D in cells and in mice. AMBRA1 loss further promotes lung cancer development in a mouse model, and low levels of AMBRA1 correlate with worse survival in lung cancer patients. Mechanistically, AMBRA1 acts as a substrate receptor for the Cullin 4 E3 ligase complex to promote ubiquitylation and proteasomal degradation of the three Cyclin D family members. Thus, AMBRA1 regulates Cyclin D protein levels and contributes to the development of cancer as well as the response of cancer cells to CDK4/6 inhibitors.
2021-02-05 | GSE146588 | GEO
Project description:The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D
| PRJNA610050 | ENA
Project description:The AMBRA1 E3 ligase adaptor regulates Cyclin D protein stability [U2OS cells]
| PRJNA670897 | ENA
Project description:The AMBRA1 E3 ligase adaptor regulates Cyclin D protein stability [U937 cells]
| PRJNA610890 | ENA
Project description:Here we describe AMBRA1 as the main regulator of Cyclin D protein degradation. We first identify AMBRA1 as the top candidate in a genome-wide CRISPR/Cas9 loss-of-function screen investigating the genetic basis of resistance to chemical CDK4/6 inhibition. AMBRA1 loss results in high protein levels of Cyclin D in cells and in mice. AMBRA1 loss further promotes lung cancer development in a mouse model, and low levels of AMBRA1 correlate with worse survival in lung cancer patients. Mechanistically, AMBRA1 acts as a substrate receptor for the Cullin 4 E3 ligase complex to promote ubiquitylation and proteasomal degradation of the three Cyclin D family members. Thus, AMBRA1 regulates Cyclin D protein levels and contributes to the development of cancer as well as the response of cancer cells to CDK4/6 inhibitors.
2021-07-24 | PXD021789 | Pride
Project description:AMBRA1 is a tumor suppressor protein that functions as a substrate receptor of the ubiquitin conjugation system with roles in autophagy and the cell cycle regulatory network. The intrinsic disorder of AMBRA1 has thus far precluded its structural determination. To solve this problem, we analyzed the dynamics of AMBRA1 using hydrogen deuterium exchange mass spectrometry (HDX-MS). The HDX results indicated that AMBRA1 is a highly flexible protein and can be stabilized upon interaction with DDB1, the adaptor of the Cullin4A/B E3 ligase. Here, we present the cryo-EM structure of AMBRA1 in complex with DDB1 at 3.08 Å resolution. The structure shows that parts of the N- and C-terminal structural regions in AMBRA1 fold together into the highly dynamic WD40 domain and reveals how DDB1 engages with AMBRA1 to create a binding scaffold for substrate recruitment. The N-terminal helix-loop-helix motif and WD40 domain of AMBRA1 associate with the double-propeller fold of DDB1. We also demonstrate that DDB1 binding-defective AMBRA1 mutants prevent ubiquitination of the substrate Cyclin D1 in vitro and increase cell cycle progression. Together, these results provide structural insights into the AMBRA1-ubiquitin ligase complex and suggest a mechanism by which AMBRA1 acts as a hub involved in various physiological processes.
2023-11-16 | PXD046056 | Pride
Project description:Ubiquitylation proteomics experiment for HEK293T cells treated with either non-targeting shRNA, or shRNA knockdown of AMBRA1 by two independent shRNA's (shAMBRA1-TRC20, and shAMBRA1-TRC36).
2021-04-22 | PXD022111 | Pride
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-02-05 | GSE159922 | GEO