Downregulation of YAP Activity Restricts P53 Hyperactivation to Promote Cell Survival in Confinement

Author:

Hemmati Farnaz1,Akinpelu Ayuba1,Song Jiyeon2,Amiri Farshad1,McDaniel Anya1,McMurray Collins1,Afthinos Alexandros3,Andreadis Stelios T.4567,Aitken Andrew V.89,Biancardi Vinicia C.89,Gerecht Sharon2,Mistriotis Panagiotis1ORCID

Affiliation:

1. Department of Chemical Engineering Auburn University Auburn AL 36849 USA

2. Department of Biomedical Engineering Duke University Durham NC 27708 USA

3. Cooper Medical School of Rowan University Camden NJ 08103 USA

4. Departments of Chemical and Biological Engineering The State University of New York Buffalo NY 14260 USA

5. Department of Biomedical Engineering University at Buffalo The State University of New York Buffalo NY 14228 USA

6. Center of Excellence in Bioinformatics and Life Sciences Buffalo NY 14203 USA

7. Center for Cell Gene and Tissue Engineering (CGTE) University at Buffalo The State University of New York Buffalo NY 14260 USA

8. Department of Anatomy Physiology and Pharmacology College of Veterinary Medicine Auburn University Auburn AL 36849 USA

9. Center for Neurosciences Initiative Auburn University Auburn AL 36849 USA

Abstract

AbstractCell migration through confining three dimensional (3D) topographies can lead to loss of nuclear envelope integrity, DNA damage, and genomic instability. Despite these detrimental phenomena, cells transiently exposed to confinement do not usually die. Whether this is also true for cells subjected to long‐term confinement remains unclear at present. To investigate this, photopatterning and microfluidics are employed to fabricate a high‐throughput device that circumvents limitations of previous cell confinement models and enables prolonged culture of single cells in microchannels with physiologically relevant length scales. The results of this study show that continuous exposure to tight confinement can trigger frequent nuclear envelope rupture events, which in turn promote P53 activation and cell apoptosis. Migrating cells eventually adapt to confinement and evade cell death by downregulating YAP activity. Reduced YAP activity, which is the consequence of confinement‐induced YAP1/2 translocation to the cytoplasm, suppresses the incidence of nuclear envelope rupture and abolishes P53‐mediated cell death. Cumulatively, this work establishes advanced, high‐throughput biomimetic models for better understanding cell behavior in health and disease, and underscores the critical role of topographical cues and mechanotransduction pathways in the regulation of cell life and death.

Funder

National Institute of General Medical Sciences

American Heart Association

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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