TY - JOUR
T1 - Cross-talk between mutant p53 and p62/SQSTM1 augments cancer cell migration by promoting the degradation of cell adhesion proteins
AU - Mukherjee, Saptaparna
AU - Maddalena, Martino
AU - Lü, YiQing
AU - Martinez, Sebastien
AU - Nataraj, Nishanth Belugali
AU - Noronha, Ashish
AU - Sinha, Sansrity
AU - Teng, Katie
AU - Cohen-Kaplan, Victoria
AU - Ziv, Tamar
AU - Arandkar, Sharathchandra
AU - Hassin, Ori
AU - Chatterjee, Rishita
AU - Pirona, Anna-Chiara
AU - Shreberk-Shaked, Michal
AU - Gershoni, Anat
AU - Aylon, Yael
AU - Elazar, Zvulun
AU - Yarden, Yosef
AU - Schramek, Daniel
AU - Oren, Moshe
PY - 2022/4/26
Y1 - 2022/4/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85128794479&partnerID=8YFLogxK
U2 - 10.1073/pnas.2119644119
DO - 10.1073/pnas.2119644119
M3 - Article
C2 - 35439056
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences
JF - Proceedings of the National Academy of Sciences
IS - 17
M1 - e2119644119
ER -