The cancer-associated, gain-of-function TP53 variant P152Lp53 activates multiple signaling pathways implicated in tumorigenesis

The Journal of Biological Chemistry
Siddharth SinghTapas K Kundu

Abstract

TP53 is the most frequently mutated tumor suppressor gene in many cancers, yet biochemical characterization of several of its reported mutations with probable biological significance have not been accomplished enough. Specifically, missense mutations in TP53 can contribute to tumorigenesis through gain-of-function of biochemical and biological properties that stimulate tumor growth. Here, we identified a relatively rare mutation leading to a proline to leucine substitution (P152L) in TP53 at the very end of its DNA-binding domain (DBD) in a sample from an Indian oral cancer patient. Although the P152Lp53 DBD alone bound to DNA, the full-length protein completely lacked binding ability at its cognate DNA motifs. Interestingly, P152Lp53 could efficiently tetramerize, and the mutation had only a limited impact on the structure and stability of full-length p53. Significantly, when we expressed this variant in a TP53-null cell line, it induced cell motility, proliferation, and invasion compared with a vector-only control. Also, enhanced tumorigenic potential was observed when P152Lp53-expressing cells were xenografted into nude mice. Investigating the effects of P152Lp53 expression on cellular pathways, we found that it is associate...Continue Reading

References

Jan 1, 1992·Genes, Chromosomes & Cancer·C Caron de Fromentel, T Soussi
Jan 1, 1992·Molecular Carcinogenesis·J E StengerP Tegtmeyer
Jul 5, 1991·Science·M HollsteinC C Harris
Aug 29, 1995·Proceedings of the National Academy of Sciences of the United States of America·M L AgarwalG R Stark
Nov 16, 1994·Journal of the National Cancer Institute·J WagnerD Malkin
Jul 1, 1993·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·G P Zambetti, A J Levine
Apr 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·P N FriedmanC Prives
Oct 11, 1996·The Journal of Biological Chemistry·P FriedlanderC Prives
Jun 17, 1998·The EMBO Journal·K G McLure, P W Lee
Jul 21, 1999·Proceedings of the National Academy of Sciences of the United States of America·K B WongA R Fersht
Nov 5, 1999·Advances in Cancer Research·P Hainaut, M Hollstein
Jan 7, 2000·The American Journal of Pathology·J F Simpson, D L Page
Mar 4, 2000·The Journal of Biological Chemistry·M SchulerD R Green
Jul 8, 2003·The Journal of Biological Chemistry·Amit Kumar MandalSiddhartha Roy
Mar 5, 2004·Breast Cancer Research and Treatment·Meghan E MinardGary E Gallick
Jul 29, 2004·Cell Cycle·Rainer K Brachmann
Aug 24, 2004·Journal of Molecular Biology·Richard L WeinbergAlan R Fersht
Oct 12, 2004·The International Journal of Biochemistry & Cell Biology·Annie Pardo, Moisés Selman
Jan 7, 2006·Nature Reviews. Cancer·Thierry SoussiChristophe Béroud
Apr 3, 2007·Oncogene·S StranoG Blandino
Sep 12, 2007·Bioinformatics·M A LarkinD G Higgins
Dec 21, 2007·The New England Journal of Medicine·M Luana PoetaWayne M Koch
Apr 16, 2008·Annual Review of Biochemistry·Andreas C Joerger, Alan R Fersht
Nov 26, 2008·Nature Reviews. Cancer·Michael Pollak
May 5, 2009·Cell·Karen H Vousden, Carol Prives
Feb 26, 2010·Cold Spring Harbor Perspectives in Biology·Magali OlivierPierre Hainaut
Feb 26, 2010·Cold Spring Harbor Perspectives in Biology·Moshe Oren, Varda Rotter
Aug 4, 2010·Cold Spring Harbor Perspectives in Biology·Rachel Beckerman, Carol Prives
Dec 29, 2010·Biomedical Research·Kazuhito YoshikawaTetsuya Moriuchi
Jun 21, 2012·Genes & Development·William A Freed-Pastor, Carol Prives
Oct 30, 2012·Bioinformatics·Alexander DobinThomas R Gingeras
Mar 30, 2013·Cancer Research·Daniele M GilkesGregg L Semenza
Dec 18, 2014·Genome Biology·Michael I LoveSimon Anders
Jan 15, 2015·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Jonathan D WassermanDavid Malkin
Jul 19, 2015·BMC Bioinformatics·Stephen W Hartley, James C Mullikin

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.