Cargando…

Pin1 modulates p63α protein stability in regulation of cell survival, proliferation and tumor formation

The homolog of p53 gene, p63, encodes multiple p63 protein isoforms. TAp63 proteins contain an N-terminal transactivation domain similar to that of p53 and function as tumor suppressors; whereas ΔNp63 isoforms, which lack the intact N-terminal transactivation domain, are associated with human tumori...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, C, Chang, D L, Yang, Z, Qi, J, Liu, R, He, H, Li, D, Xiao, Z X
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877541/
https://www.ncbi.nlm.nih.gov/pubmed/24309930
http://dx.doi.org/10.1038/cddis.2013.468
_version_ 1782297671190446080
author Li, C
Chang, D L
Yang, Z
Qi, J
Liu, R
He, H
Li, D
Xiao, Z X
author_facet Li, C
Chang, D L
Yang, Z
Qi, J
Liu, R
He, H
Li, D
Xiao, Z X
author_sort Li, C
collection PubMed
description The homolog of p53 gene, p63, encodes multiple p63 protein isoforms. TAp63 proteins contain an N-terminal transactivation domain similar to that of p53 and function as tumor suppressors; whereas ΔNp63 isoforms, which lack the intact N-terminal transactivation domain, are associated with human tumorigenesis. Accumulating evidence demonstrating the important roles of p63 in development and cancer development, the regulation of p63 proteins, however, is not fully understood. In this study, we show that peptidyl-prolyl isomerase Pin1 directly binds to and stabilizes TAp63α and ΔNp63α via inhibiting the proteasomal degradation mediated by E3 ligase WWP1. We further show that Pin1 specifically interacts with T(538)P which is adjacent to the P(550)PxY(543) motif, and disrupts p63α–WWP1 interaction. In addition, while Pin1 enhances TAp63α-mediated apoptosis, it promotes ΔNp63α-induced cell proliferation. Furthermore, knockdown of Pin1 in FaDu cells inhibits tumor formation in nude mice, which is rescued by simultaneous knockdown of WWP1 or ectopic expression of ΔNp63α. Moreover, overexpression of Pin1 correlates with increased expression of ΔNp63α in human oral squamous cell carcinoma samples. Together, these results suggest that Pin1-mediated modulation of ΔNp63α may have a causative role in tumorigenesis.
format Online
Article
Text
id pubmed-3877541
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-38775412014-01-02 Pin1 modulates p63α protein stability in regulation of cell survival, proliferation and tumor formation Li, C Chang, D L Yang, Z Qi, J Liu, R He, H Li, D Xiao, Z X Cell Death Dis Original Article The homolog of p53 gene, p63, encodes multiple p63 protein isoforms. TAp63 proteins contain an N-terminal transactivation domain similar to that of p53 and function as tumor suppressors; whereas ΔNp63 isoforms, which lack the intact N-terminal transactivation domain, are associated with human tumorigenesis. Accumulating evidence demonstrating the important roles of p63 in development and cancer development, the regulation of p63 proteins, however, is not fully understood. In this study, we show that peptidyl-prolyl isomerase Pin1 directly binds to and stabilizes TAp63α and ΔNp63α via inhibiting the proteasomal degradation mediated by E3 ligase WWP1. We further show that Pin1 specifically interacts with T(538)P which is adjacent to the P(550)PxY(543) motif, and disrupts p63α–WWP1 interaction. In addition, while Pin1 enhances TAp63α-mediated apoptosis, it promotes ΔNp63α-induced cell proliferation. Furthermore, knockdown of Pin1 in FaDu cells inhibits tumor formation in nude mice, which is rescued by simultaneous knockdown of WWP1 or ectopic expression of ΔNp63α. Moreover, overexpression of Pin1 correlates with increased expression of ΔNp63α in human oral squamous cell carcinoma samples. Together, these results suggest that Pin1-mediated modulation of ΔNp63α may have a causative role in tumorigenesis. Nature Publishing Group 2013-12 2013-12-05 /pmc/articles/PMC3877541/ /pubmed/24309930 http://dx.doi.org/10.1038/cddis.2013.468 Text en Copyright © 2013 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
Li, C
Chang, D L
Yang, Z
Qi, J
Liu, R
He, H
Li, D
Xiao, Z X
Pin1 modulates p63α protein stability in regulation of cell survival, proliferation and tumor formation
title Pin1 modulates p63α protein stability in regulation of cell survival, proliferation and tumor formation
title_full Pin1 modulates p63α protein stability in regulation of cell survival, proliferation and tumor formation
title_fullStr Pin1 modulates p63α protein stability in regulation of cell survival, proliferation and tumor formation
title_full_unstemmed Pin1 modulates p63α protein stability in regulation of cell survival, proliferation and tumor formation
title_short Pin1 modulates p63α protein stability in regulation of cell survival, proliferation and tumor formation
title_sort pin1 modulates p63α protein stability in regulation of cell survival, proliferation and tumor formation
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877541/
https://www.ncbi.nlm.nih.gov/pubmed/24309930
http://dx.doi.org/10.1038/cddis.2013.468
work_keys_str_mv AT lic pin1modulatesp63aproteinstabilityinregulationofcellsurvivalproliferationandtumorformation
AT changdl pin1modulatesp63aproteinstabilityinregulationofcellsurvivalproliferationandtumorformation
AT yangz pin1modulatesp63aproteinstabilityinregulationofcellsurvivalproliferationandtumorformation
AT qij pin1modulatesp63aproteinstabilityinregulationofcellsurvivalproliferationandtumorformation
AT liur pin1modulatesp63aproteinstabilityinregulationofcellsurvivalproliferationandtumorformation
AT heh pin1modulatesp63aproteinstabilityinregulationofcellsurvivalproliferationandtumorformation
AT lid pin1modulatesp63aproteinstabilityinregulationofcellsurvivalproliferationandtumorformation
AT xiaozx pin1modulatesp63aproteinstabilityinregulationofcellsurvivalproliferationandtumorformation