Mutant p53 promotes RCP-dependent chemoresistance coinciding with increased delivery of P-glycoprotein to the plasma membrane
von Grabowiecki, Yannick
Norman, J. C.
Le Quesne, J.
AffiliationMRC Toxicology Unit, University of Cambridge, Cambridge, UK.
MetadataShow full item record
AbstractTP53 is the most frequently mutated gene in cancers. Mutations lead to loss of p53 expression or expression of a mutant protein. Mutant p53 proteins commonly lose wild-type function, but can also acquire novel functions in promoting metastasis and chemoresistance. Previously, we uncovered a role for Rab-coupling protein (RCP) in mutant p53-dependent invasion. RCP promotes endosomal recycling and signalling of integrins and receptor tyrosine kinases. In a screen to identify novel RCP-interacting proteins, we discovered P-glycoprotein (P-gp). Thus, we hypothesised that mutant p53 could promote chemoresistance through RCP-dependent recycling of P-gp. The interaction between RCP and P-gp was verified endogenously and loss of RCP or mutant p53 rendered cells more sensitive to cisplatin and etoposide. In mutant p53 cells we detected an RCP-dependent delivery of P-gp to the plasma membrane upon drug treatment and decreased retention of P-gp substrates. A co-localisation of P-gp and RCP was seen in mutant p53 cells, but not in p53-null cells upon chemotherapeutic exposure. In conclusion, mutant p53 expression enhanced co-localisation of P-gp and RCP to allow for rapid delivery of P-gp to the plasma membrane and increased resistance to chemotherapeutics.
CitationPhatak V, von Grabowiecki Y, Janus J, Officer L, Behan C, Aschauer L, et al. Mutant p53 promotes RCP-dependent chemoresistance coinciding with increased delivery of P-glycoprotein to the plasma membrane. Cell Death Dis. 2021;12(2):207.
JournalCell Death and Disease
- Mutant p53 drives invasion by promoting integrin recycling.
- Authors: Muller PA, Caswell PT, Doyle B, Iwanicki MP, Tan EH, Karim S, Lukashchuk N, Gillespie DA, Ludwig RL, Gosselin P, Cromer A, Brugge JS, Sansom OJ, Norman JC, Vousden KH
- Issue date: 2009 Dec 24
- Mutant p53 enhances MET trafficking and signalling to drive cell scattering and invasion.
- Authors: Muller PA, Trinidad AG, Timpson P, Morton JP, Zanivan S, van den Berghe PV, Nixon C, Karim SA, Caswell PT, Noll JE, Coffill CR, Lane DP, Sansom OJ, Neilsen PM, Norman JC, Vousden KH
- Issue date: 2013 Mar 7
- Mutant p53 Drives Cancer Metastasis via RCP-Mediated Hsp90α Secretion.
- Authors: Zhang S, Wang C, Ma B, Xu M, Xu S, Liu J, Tian Y, Fu Y, Luo Y
- Issue date: 2020 Jul 7
- Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration.
- Authors: Rainero E, Caswell PT, Muller PA, Grindlay J, McCaffrey MW, Zhang Q, Wakelam MJ, Vousden KH, Graziani A, Norman JC
- Issue date: 2012 Jan 23
- Rab coupling protein mediated endosomal recycling of N-cadherin influences cell motility.
- Authors: Lindsay AJ, McCaffrey MW
- Issue date: 2017 Dec 1