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Contact inhibition controls cell survival and proliferation via YAP/TAZ-autophagy axis.

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Pavel, Mariana 
Renna, Maurizio 
Park, So Jung 
Menzies, Fiona M 
Ricketts, Thomas 


Contact inhibition enables noncancerous cells to cease proliferation and growth when they contact each other. This characteristic is lost when cells undergo malignant transformation, leading to uncontrolled proliferation and solid tumor formation. Here we report that autophagy is compromised in contact-inhibited cells in 2D or 3D-soft extracellular matrix cultures. In such cells, YAP/TAZ fail to co-transcriptionally regulate the expression of myosin-II genes, resulting in the loss of F-actin stress fibers, which impairs autophagosome formation. The decreased proliferation resulting from contact inhibition is partly autophagy-dependent, as is their increased sensitivity to hypoxia and glucose starvation. These findings define how mechanically repressed YAP/TAZ activity impacts autophagy to contribute to core phenotypes resulting from high cell confluence that are lost in various cancers.



Actin Cytoskeleton, Actins, Acyltransferases, Adaptor Proteins, Signal Transducing, Animals, Apoptosis, Autophagosomes, Autophagy, CapZ Actin Capping Protein, Cell Count, Cell Line, Tumor, Cell Proliferation, Cell Survival, Contact Inhibition, Epithelial Cells, Extracellular Matrix, Fibroblasts, Gene Knockdown Techniques, Glucose, HeLa Cells, Humans, Hypoxia, Mice, Myosin Type II, Phosphoproteins, Signal Transduction, Transcription Factors, YAP-Signaling Proteins

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Nat Commun

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Springer Science and Business Media LLC
Wellcome Trust (095317/Z/11/Z)
Cambridge University Hospitals NHS Foundation Trust (CUH) (RG50822)
Wellcome Trust (100140/Z/12/Z)
European Commission (264508)
This work was supported by the Wellcome Trust (Principal Research Fellowship to DCR (095317/Z/11/Z)), a Strategic Grant to Cambridge Institute for Medical Research (100140/Z/12/Z), the UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society), MRC and Sackler Foundation (doctoral training grant RG70550 to ACL), NIHR Biomedical Research Unit in Dementia at Addenbrooke’s Hospital, the Treat PolyQ project (European community’s Seventh Framework Programme under grant agreement No. 264508), a Romanian grant of Ministery of Research and Innovation CNCS –UEFISCDI, project number PN-III-P1-1.1-PD-2016-1291, within PNCDI III (to MP).