Distinct p53 response profiles in transgenic mouse models of thyroid-specific PBF and PTTG expression

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Distinct p53 response profiles in transgenic mouse models of thyroid-specific PBF and PTTG expression. / Read, Martin; Fong, Jim; Imruetaicharoenchoke, Waraporn; Modasia, Bhavika; Lewy, Gregory; Ryan, Gavin; Sharma, Neil; Smith, Vicki; Watkinson, John; Boelaert, Kristien; McCabe, Christopher.

In: Endocrine Abstracts, Vol. 38, P149, 11.2015.

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Read, Martin ; Fong, Jim ; Imruetaicharoenchoke, Waraporn ; Modasia, Bhavika ; Lewy, Gregory ; Ryan, Gavin ; Sharma, Neil ; Smith, Vicki ; Watkinson, John ; Boelaert, Kristien ; McCabe, Christopher. / Distinct p53 response profiles in transgenic mouse models of thyroid-specific PBF and PTTG expression. In: Endocrine Abstracts. 2015 ; Vol. 38.

Bibtex

@article{94b65b3da9df4ddd83c453e552c2481a,
title = "Distinct p53 response profiles in transgenic mouse models of thyroid-specific PBF and PTTG expression",
abstract = "Functional disruption of the tumour suppressor p53 has a critical role in promoting the development of most cancers. The proto-oncogenes PBF and PTTG1 both regulate p53 activity, but the relative contribution of each gene in influencing p53 function has not been delineated, especially in thyroid cancer where both proto-oncogenes are commonly overexpressed. To better understand the interplay between PTTG1, PBF and p53 in vivo, we examined p53 responses in primary thyrocytes cultured from transgenic mice overexpressing PBF (PBF-Tg) and PTTG1 (PTTG-Tg), either singly or in combination in a bi-transgenic murine model (Bi-Tg). Western blotting showed that p53 and γ-H2AX protein levels were elevated in PTTG1-Tg and BI-Tg thyrocytes (>2-fold; P<0.05). In contrast, no significant increase was observed in p53 or γ-H2AX levels in PBF-Tg thyrocytes compared to WT (P=NS). Consistent with this, a greater proportion of a panel of p53-responsive DNA repair genes were significantly down-regulated in PTTG1-Tg (30/83 genes) and BI-Tg (30/83 genes) than in PBF-Tg thyrocytes (12/83 genes). A differential p53 response was further evident following gamma-irradiation of cells, with fewer significant mRNA changes occurring in PTTG1-Tg (0/10 genes; P=NS) and BI-Tg (4/10 genes; P<0.05) than in WT primary thyrocytes (10/10 genes; P<0.01). By comparison, irradiation of PBF-Tg thyrocytes gave the greatest reduction in mRNA levels (6/10 genes; P<0.05) for genes such as Chek1 (4.4-fold; P<0.01) and Rad51 (8.4-fold; P<0.01). We therefore examined potential associations between PBF and DNA repair genes in human thyroid tumours. Importantly, a significant correlation was apparent between PBF and Chek1 (R=0.44; P<0.05; N=22), Fancg (R=0.78; P<0.001; N=22) and Mutyh (R=0.62; P<0.05; N=22). Together our data reveal for the first time that PBF and PTTG1 mediate distinct p53 response profiles in vivo. These results offer important insights for understanding the impact of proto-oncogenes on thyroid tumorigenesis and for identifying new tumour biomarkers.",
author = "Martin Read and Jim Fong and Waraporn Imruetaicharoenchoke and Bhavika Modasia and Gregory Lewy and Gavin Ryan and Neil Sharma and Vicki Smith and John Watkinson and Kristien Boelaert and Christopher McCabe",
year = "2015",
month = nov,
doi = "10.1530/endoabs.38.P149",
language = "English",
volume = "38",
journal = "Endocrine Abstracts",
issn = "1470-3947",
publisher = "BioScientifica",

}

RIS

TY - JOUR

T1 - Distinct p53 response profiles in transgenic mouse models of thyroid-specific PBF and PTTG expression

AU - Read, Martin

AU - Fong, Jim

AU - Imruetaicharoenchoke, Waraporn

AU - Modasia, Bhavika

AU - Lewy, Gregory

AU - Ryan, Gavin

AU - Sharma, Neil

AU - Smith, Vicki

AU - Watkinson, John

AU - Boelaert, Kristien

AU - McCabe, Christopher

PY - 2015/11

Y1 - 2015/11

N2 - Functional disruption of the tumour suppressor p53 has a critical role in promoting the development of most cancers. The proto-oncogenes PBF and PTTG1 both regulate p53 activity, but the relative contribution of each gene in influencing p53 function has not been delineated, especially in thyroid cancer where both proto-oncogenes are commonly overexpressed. To better understand the interplay between PTTG1, PBF and p53 in vivo, we examined p53 responses in primary thyrocytes cultured from transgenic mice overexpressing PBF (PBF-Tg) and PTTG1 (PTTG-Tg), either singly or in combination in a bi-transgenic murine model (Bi-Tg). Western blotting showed that p53 and γ-H2AX protein levels were elevated in PTTG1-Tg and BI-Tg thyrocytes (>2-fold; P<0.05). In contrast, no significant increase was observed in p53 or γ-H2AX levels in PBF-Tg thyrocytes compared to WT (P=NS). Consistent with this, a greater proportion of a panel of p53-responsive DNA repair genes were significantly down-regulated in PTTG1-Tg (30/83 genes) and BI-Tg (30/83 genes) than in PBF-Tg thyrocytes (12/83 genes). A differential p53 response was further evident following gamma-irradiation of cells, with fewer significant mRNA changes occurring in PTTG1-Tg (0/10 genes; P=NS) and BI-Tg (4/10 genes; P<0.05) than in WT primary thyrocytes (10/10 genes; P<0.01). By comparison, irradiation of PBF-Tg thyrocytes gave the greatest reduction in mRNA levels (6/10 genes; P<0.05) for genes such as Chek1 (4.4-fold; P<0.01) and Rad51 (8.4-fold; P<0.01). We therefore examined potential associations between PBF and DNA repair genes in human thyroid tumours. Importantly, a significant correlation was apparent between PBF and Chek1 (R=0.44; P<0.05; N=22), Fancg (R=0.78; P<0.001; N=22) and Mutyh (R=0.62; P<0.05; N=22). Together our data reveal for the first time that PBF and PTTG1 mediate distinct p53 response profiles in vivo. These results offer important insights for understanding the impact of proto-oncogenes on thyroid tumorigenesis and for identifying new tumour biomarkers.

AB - Functional disruption of the tumour suppressor p53 has a critical role in promoting the development of most cancers. The proto-oncogenes PBF and PTTG1 both regulate p53 activity, but the relative contribution of each gene in influencing p53 function has not been delineated, especially in thyroid cancer where both proto-oncogenes are commonly overexpressed. To better understand the interplay between PTTG1, PBF and p53 in vivo, we examined p53 responses in primary thyrocytes cultured from transgenic mice overexpressing PBF (PBF-Tg) and PTTG1 (PTTG-Tg), either singly or in combination in a bi-transgenic murine model (Bi-Tg). Western blotting showed that p53 and γ-H2AX protein levels were elevated in PTTG1-Tg and BI-Tg thyrocytes (>2-fold; P<0.05). In contrast, no significant increase was observed in p53 or γ-H2AX levels in PBF-Tg thyrocytes compared to WT (P=NS). Consistent with this, a greater proportion of a panel of p53-responsive DNA repair genes were significantly down-regulated in PTTG1-Tg (30/83 genes) and BI-Tg (30/83 genes) than in PBF-Tg thyrocytes (12/83 genes). A differential p53 response was further evident following gamma-irradiation of cells, with fewer significant mRNA changes occurring in PTTG1-Tg (0/10 genes; P=NS) and BI-Tg (4/10 genes; P<0.05) than in WT primary thyrocytes (10/10 genes; P<0.01). By comparison, irradiation of PBF-Tg thyrocytes gave the greatest reduction in mRNA levels (6/10 genes; P<0.05) for genes such as Chek1 (4.4-fold; P<0.01) and Rad51 (8.4-fold; P<0.01). We therefore examined potential associations between PBF and DNA repair genes in human thyroid tumours. Importantly, a significant correlation was apparent between PBF and Chek1 (R=0.44; P<0.05; N=22), Fancg (R=0.78; P<0.001; N=22) and Mutyh (R=0.62; P<0.05; N=22). Together our data reveal for the first time that PBF and PTTG1 mediate distinct p53 response profiles in vivo. These results offer important insights for understanding the impact of proto-oncogenes on thyroid tumorigenesis and for identifying new tumour biomarkers.

U2 - 10.1530/endoabs.38.P149

DO - 10.1530/endoabs.38.P149

M3 - Abstract

VL - 38

JO - Endocrine Abstracts

JF - Endocrine Abstracts

SN - 1470-3947

M1 - P149

ER -