Cross-talk between mutant p53 and p62/SQSTM1 augments cancer cell migration by promoting the degradation of cell adhesion proteins.

Autor: Mukherjee S; Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel., Maddalena M; Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel., Lü Y; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5S 1A8, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada., Martinez S; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5S 1A8, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada., Nataraj NB; Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel., Noronha A; Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel., Sinha S; Department of Biomolecular Science, Weizmann Institute of Science, 7610001 Rehovot, Israel., Teng K; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5S 1A8, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada., Cohen-Kaplan V; Technion Integrated Cancer Center, The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, 3109601 Haifa, Israel., Ziv T; Smoler Proteomic Center, Faculty of Biology, Technion-Israel Institute of Technology, 3200003 Haifa, Israel., Arandkar S; Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel.; Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, 410210 Kharghar, Navi Mumbai, India., Hassin O; Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel., Chatterjee R; Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel., Pirona AC; Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel., Shreberk-Shaked M; Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel., Gershoni A; Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel., Aylon Y; Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel., Elazar Z; Department of Biomolecular Science, Weizmann Institute of Science, 7610001 Rehovot, Israel., Yarden Y; Department of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, Israel., Schramek D; Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5S 1A8, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada., Oren M; Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Apr 26; Vol. 119 (17), pp. e2119644119. Date of Electronic Publication: 2022 Apr 19.
DOI: 10.1073/pnas.2119644119
Abstrakt: 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 p53R273H is the most frequent p53 mutant. We now report that p53R273H, but not the p53R175H hotspot mutant, interacts with SQSTM1/p62 and promotes cancer cell migration and invasion in a p62-dependent manner. Mechanistically, the p53R273H-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 p53R273H-p62 axis. These findings define a mechanism of mutp53 GOF.
Databáze: MEDLINE