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

被引：19

作者：

Mukherjee, Saptaparna ^{[1
]}

Maddalena, Martino ^{[1
]}

Lu, YiQing ^{[2
,3
]}

Martinez, Sebastien ^{[2
,3
]}

Nataraj, Nishanth Belugali ^{[4
]}

Noronha, Ashish ^{[4
]}

Sinha, Sansrity ^{[5
]}

Teng, Katie ^{[3
]}

Cohen-Kaplan, Victoria ^{[6
]}

Ziv, Tamar ^{[7
]}

Arandkar, Sharathchandra ^{[1
,8
]}

Hassin, Ori ^{[1
]}

Chatterjee, Rishita ^{[4
]}

Pirona, Anna-Chiara ^{[1
]}

Shreberk-Shaked, Michal ^{[1
]}

Gershoni, Anat ^{[1
]}

Aylon, Yael ^{[1
]}

Elazar, Zvulun ^{[5
]}

Yarden, Yosef ^{[4
]}

Schramek, Daniel ^{[2
,3
]}

Oren, Moshe ^{[1
]}

机构：

[1] Weizmann Inst Sci, Dept Mol Cell Biol, IL-7610001 Rehovot, Israel

[2] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Ctr Mol & Syst Biol, Toronto, ON M5S IA8, Canada

[3] Univ Toronto, Dept Mol Genet, Toronto, ON M5S IA8, Canada

[4] Weizmann Inst Sci, Dept Biol Regulat, IL-7610001 Rehovot, Israel

[5] Weizmann Inst Sci, Dept Biomol Sci, IL-7610001 Rehovot, Israel

[6] Techn Israel Inst Technol, Rappaport Fac Med & Res Inst, Techn Integrated Canc Ctr, IL-3109601 Haifa, Israel

[7] Techn Israel Inst Technol, Smoler Prote Ctr, Fac Biol, IL-3200003 Haifa, Israel

[8] Tata Mem Hosp, Advanced Ctr Treatment Res & Educ Canc, Navi Mumbai 410210, India

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2022年 / 119卷 / 17期

基金：

加拿大健康研究院; 以色列科学基金会;

关键词：

mutant p53; p62; protein-protein interaction; migration; cell adhesion; UP-REGULATION; GAP-JUNCTIONS; TP53; GENE; AUTOPHAGY; P62; INVASION; MITOPHAGY; APOPTOSIS; REVEALS; COMPLEX;

D O I：

10.1073/pnas.2119644119

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：12

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