Proteomics

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The AMBRA1 E3 ligase adaptor regulates Cyclin D protein stability

ABSTRACT: 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.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Tibia, Epithelial Cell

DISEASE(S): Bone Osteosarcoma

SUBMITTER: Janos Demeter  

LAB HEAD: Julien Sage

PROVIDER: PXD021789 | Pride | 2021-07-24

REPOSITORIES: Pride

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Publications

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<sup>1</sup>. 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 unch  ...[more]

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