Wild-type p53 oligomerizes more efficiently than p53 hot-spot mutants and overcomes mutant p53 gain-of-function via a "dominant-positive" mechanism

Oncotarget
Dawid WalerychAlicja Zylicz

Abstract

Human p53 protein acts as a transcription factor predominantly in a tetrameric form. Single residue changes, caused by hot-spot mutations of the TP53 gene in human cancer, transform wild-type (wt) p53 tumor suppressor proteins into potent oncoproteins - with gain-of-function, tumor-promoting activity. Oligomerization of p53 allows for a direct interplay between wt and mutant p53 proteins if both are present in the same cells - where a mutant p53's dominant-negative effect known to inactivate wt p53, co-exists with an opposite mechanism - a "dominant-positive" suppression of the mutant p53's gain-of-function activity by wt p53. In this study we determine the oligomerization efficiency of wt and mutant p53 in living cells using FRET-based assays and describe wt p53 to be more efficient than mutant p53 in entering p53 oligomers. The biased p53 oligomerization helps to interpret earlier reports of a low efficiency of the wt p53 inactivation via the dominant-negative effect, while it also implies that the "dominant-positive" effect may be more pronounced. Indeed, we show that at similar wt:mutant p53 concentrations in cells - the mutant p53 gain-of-function stimulation of gene transcription and cell migration is more efficiently inh...Continue Reading

References

Apr 21, 1995·International Journal of Cancer. Journal International Du Cancer·B TopS Rodenhuis
Oct 20, 1993·Journal of the National Cancer Institute·N M NavoneC J Conti
Apr 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·P N FriedmanC Prives
Jun 17, 1998·The EMBO Journal·K G McLure, P W Lee
Mar 20, 2002·Nature Reviews. Cancer·A N Bullock, A R Fersht
May 27, 2003·Cell Calcium·Hemasse AmiriMichael Schaefer
Jun 27, 2003·Proceedings of the National Academy of Sciences of the United States of America·Shunsuke KatoChikashi Ishioka
Apr 3, 2004·Molecular and Cellular Biology·Wan Mui ChanRandy Y C Poon
Mar 31, 2005·Biochemical and Biophysical Research Communications·Motohiro YamauchiMasami Watanabe
May 17, 2008·Genes & Development·Tamara TerzianGuillermina Lozano
Aug 12, 2009·Proceedings of the National Academy of Sciences of the United States of America·Eviatar NatanAlan R Fersht
Apr 1, 2007·Journal of Biological Physics·Valerică Raicu
Sep 19, 2009·The EMBO Journal·Juan José FungBrian K Kobilka
Nov 26, 2009·Proceedings of the National Academy of Sciences of the United States of America·Fang HuangAlan R Fersht
Jan 13, 2010·Cell·Patricia A J MullerKaren H Vousden
Apr 20, 2010·Journal of Biomolecular Screening·Jeanne M Dudek, Robert A Horton
Jul 14, 2010·Nature Chemical Biology·Laura AlbizuThierry Durroux
Nov 26, 2010·Nucleic Acids Research·Sridharan RajagopalanAlan R Fersht
Feb 24, 2011·Molecular Cancer Research : MCR·Paola MontiGilberto Fronza
Mar 30, 2011·Nature Chemical Biology·Jie XuJoost Schymkowitz
Jun 15, 2011·BMC Cancer·Ewelina Stoczynska-FidelusPiotr Rieske
Jul 19, 2011·Nucleic Acids Research·Ricardo AramayoElena V Orlova
Sep 21, 2011·Molecular and Cellular Biology·Kang LiuWeei-Chin Lin
Jul 24, 2012·Carcinogenesis·Dawid WalerychGiannino Del Sal
Nov 15, 2012·Methods in Molecular Biology·W Andrew YeudallSumitra Deb
Sep 6, 2013·Proceedings of the National Academy of Sciences of the United States of America·Giorgio GagliaGalit Lahav
Jan 1, 2014·The Journal of Pathology·Neha ParikhLawrence A Donehower

❮ Previous
Next ❯

Citations

Dec 11, 2019·International Journal of Molecular Sciences·Yan SteinRonit Aloni-Grinstein
Sep 3, 2020·Genes & Development·Jovanka Gencel-Augusto, Guillermina Lozano
Nov 8, 2020·Carcinogenesis·Yan SteinVarda Rotter

❮ Previous
Next ❯

Methods Mentioned

BETA
FRET
confocal microscopy
transfections
transfection
co-immunoprecipitaion
co-IP
Confocal
PCR
scraping

Software Mentioned

Graph Pad Prism
Leica
ImageJ

Related Concepts

Related Feeds

Cell Migration in Cancer and Metastasis

Migration of cancer cells into surrounding tissue and the vasculature is an initial step in tumor metastasis. Discover the latest research on cell migration in cancer and metastasis here.

Cell Migration

Cell migration is involved in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. Here is the latest research.