Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 17, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2119644119
Keywords
mutant p53; p62; protein-protein interaction; migration; cell adhesion
Categories
Funding
- Canadian Institutes of Health Research
- International Development Research Centre
- Israel Science Foundation
- Azrieli Foundation
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Thompson Family Foundation
- Moross Integrated Cancer Center
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The p53R273H mutant interacts with SQSTM1/p62 and promotes cancer cell migration and invasion in a p62-dependent manner by driving the proteasomal degradation of cell junction-associated proteins.
Missense mutations in the p53 tumor suppressor abound in human cancer. Common (hotspot) mutations endow mutant p53 (mutp53) proteins with oncogenic gain of function (GOF), including enhanced cell migration and invasiveness, favoring cancer progression. GOF is usually attributed to transcriptional effects of mutp53. To elucidate transcription-independent effects of mutp53, we characterized the protein interactome of the p53R273H mutant in cells derived from pancreatic ductal adenocarcinoma (PDAC), where p53(R273H) is the most frequent p53 mutant. We now report that p53R273H, but not the p53(R175H) hotspot mutant, interacts with SQSTM1/p62 and promotes cancer cell migration and invasion in a p62-dependent manner. Mechanistically, the p53(R273H)-p62 axis drives the proteasomal degradation of several cell junction-associated proteins, including the gap junction protein Connexin 43, facilitating scattered cell migration. Concordantly, down-regulation of Connexin 43 augments PDAC cell migration, while its forced overexpression blunts the promigratory effect of the p53(R273H)-p62 axis. These findings define a mechanism of mutp53 GOF.
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