Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment

Martin L. Read, Greg D. Lewy, Jim C.W. Fong, Neil Sharma, Robert I. Seed, Vicki E. Smith, Erica Gentilin, Adrian Warfield, Margaret C. Eggo, Jeffrey A. Knauf, Wendy E. Leadbeater, John C. Watkinson, Jayne A. Franklyn, Kristien Boelaert, Christopher J. McCabe*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Pituitary tumor transforming gene (PTTG)-binding factor (PBF or PTTG1IP) is a little characterized protooncogene that has been implicated in the etiology of breast and thyroid tumors. In this study, we created a murine transgenic model to target PBF expression to the thyroid gland (PBF-Tg mice) and found that these mice exhibited normal thyroid function, but a striking enlargement of the thyroid gland associated with hyperplastic and macrofollicular lesions. Expression of the sodium iodide symporter (NIS), a gene essential to the radioiodine ablation of thyroid hyperplasia, neoplasia, and metastasis, was also potently inhibited in PBF-Tg mice. Critically, iodide uptake was repressed in primary thyroid cultures from PBF-Tg mice, which could be rescued by PBF depletion. PBF-Tg thyroids exhibited upregulation of Akt and the TSH receptor (TSHR), each known regulators of thyrocyte proliferation, along with upregulation of the downstream proliferative marker cyclin D1. We extended and confirmed findings from the mouse model by examining PBF expression in human multinodular goiters (MNG), a hyperproliferative thyroid disorder, where PBF and TSHR was strongly upregulated relative to normal thyroid tissue. Furthermore, we showed that depleting PBF in human primary thyrocytes was sufficient to increase radioiodine uptake. Together, our findings indicate that overexpression of PBF causes thyroid cell proliferation, macrofollicular lesions, and hyperplasia, as well as repression of the critical therapeutic route for radioiodide uptake.

Original languageEnglish
Pages (from-to)6153-6164
Number of pages12
JournalCancer Research
Volume71
Issue number19
DOIs
Publication statusPublished - 1 Oct 2011

Fingerprint

Proto-Oncogenes
Thyroid Gland
Growth
Thyrotropin Receptors
Hyperplasia
Up-Regulation
Cyclin D1
Essential Genes
Goiter
Pituitary Neoplasms
Iodides
Oncogenes
Cell Proliferation
Breast Neoplasms
Neoplasm Metastasis

Bibliographical note

©2011 American Association for Cancer Research

Cite this

Read, M. L., Lewy, G. D., Fong, J. C. W., Sharma, N., Seed, R. I., Smith, V. E., ... McCabe, C. J. (2011). Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment. Cancer Research, 71(19), 6153-6164. https://doi.org/10.1158/0008-5472.CAN-11-0720
Read, Martin L. ; Lewy, Greg D. ; Fong, Jim C.W. ; Sharma, Neil ; Seed, Robert I. ; Smith, Vicki E. ; Gentilin, Erica ; Warfield, Adrian ; Eggo, Margaret C. ; Knauf, Jeffrey A. ; Leadbeater, Wendy E. ; Watkinson, John C. ; Franklyn, Jayne A. ; Boelaert, Kristien ; McCabe, Christopher J. / Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment. In: Cancer Research. 2011 ; Vol. 71, No. 19. pp. 6153-6164.
@article{7c3836b02f804cd59839dc4fa3ad2c1d,
title = "Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment",
abstract = "Pituitary tumor transforming gene (PTTG)-binding factor (PBF or PTTG1IP) is a little characterized protooncogene that has been implicated in the etiology of breast and thyroid tumors. In this study, we created a murine transgenic model to target PBF expression to the thyroid gland (PBF-Tg mice) and found that these mice exhibited normal thyroid function, but a striking enlargement of the thyroid gland associated with hyperplastic and macrofollicular lesions. Expression of the sodium iodide symporter (NIS), a gene essential to the radioiodine ablation of thyroid hyperplasia, neoplasia, and metastasis, was also potently inhibited in PBF-Tg mice. Critically, iodide uptake was repressed in primary thyroid cultures from PBF-Tg mice, which could be rescued by PBF depletion. PBF-Tg thyroids exhibited upregulation of Akt and the TSH receptor (TSHR), each known regulators of thyrocyte proliferation, along with upregulation of the downstream proliferative marker cyclin D1. We extended and confirmed findings from the mouse model by examining PBF expression in human multinodular goiters (MNG), a hyperproliferative thyroid disorder, where PBF and TSHR was strongly upregulated relative to normal thyroid tissue. Furthermore, we showed that depleting PBF in human primary thyrocytes was sufficient to increase radioiodine uptake. Together, our findings indicate that overexpression of PBF causes thyroid cell proliferation, macrofollicular lesions, and hyperplasia, as well as repression of the critical therapeutic route for radioiodide uptake.",
author = "Read, {Martin L.} and Lewy, {Greg D.} and Fong, {Jim C.W.} and Neil Sharma and Seed, {Robert I.} and Smith, {Vicki E.} and Erica Gentilin and Adrian Warfield and Eggo, {Margaret C.} and Knauf, {Jeffrey A.} and Leadbeater, {Wendy E.} and Watkinson, {John C.} and Franklyn, {Jayne A.} and Kristien Boelaert and McCabe, {Christopher J.}",
note = "{\circledC}2011 American Association for Cancer Research",
year = "2011",
month = "10",
day = "1",
doi = "10.1158/0008-5472.CAN-11-0720",
language = "English",
volume = "71",
pages = "6153--6164",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "19",

}

Read, ML, Lewy, GD, Fong, JCW, Sharma, N, Seed, RI, Smith, VE, Gentilin, E, Warfield, A, Eggo, MC, Knauf, JA, Leadbeater, WE, Watkinson, JC, Franklyn, JA, Boelaert, K & McCabe, CJ 2011, 'Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment', Cancer Research, vol. 71, no. 19, pp. 6153-6164. https://doi.org/10.1158/0008-5472.CAN-11-0720

Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment. / Read, Martin L.; Lewy, Greg D.; Fong, Jim C.W.; Sharma, Neil; Seed, Robert I.; Smith, Vicki E.; Gentilin, Erica; Warfield, Adrian; Eggo, Margaret C.; Knauf, Jeffrey A.; Leadbeater, Wendy E.; Watkinson, John C.; Franklyn, Jayne A.; Boelaert, Kristien; McCabe, Christopher J.

In: Cancer Research, Vol. 71, No. 19, 01.10.2011, p. 6153-6164.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Proto-oncogene PBF/PTTG1IP regulates thyroid cell growth and represses radioiodide treatment

AU - Read, Martin L.

AU - Lewy, Greg D.

AU - Fong, Jim C.W.

AU - Sharma, Neil

AU - Seed, Robert I.

AU - Smith, Vicki E.

AU - Gentilin, Erica

AU - Warfield, Adrian

AU - Eggo, Margaret C.

AU - Knauf, Jeffrey A.

AU - Leadbeater, Wendy E.

AU - Watkinson, John C.

AU - Franklyn, Jayne A.

AU - Boelaert, Kristien

AU - McCabe, Christopher J.

N1 - ©2011 American Association for Cancer Research

PY - 2011/10/1

Y1 - 2011/10/1

N2 - Pituitary tumor transforming gene (PTTG)-binding factor (PBF or PTTG1IP) is a little characterized protooncogene that has been implicated in the etiology of breast and thyroid tumors. In this study, we created a murine transgenic model to target PBF expression to the thyroid gland (PBF-Tg mice) and found that these mice exhibited normal thyroid function, but a striking enlargement of the thyroid gland associated with hyperplastic and macrofollicular lesions. Expression of the sodium iodide symporter (NIS), a gene essential to the radioiodine ablation of thyroid hyperplasia, neoplasia, and metastasis, was also potently inhibited in PBF-Tg mice. Critically, iodide uptake was repressed in primary thyroid cultures from PBF-Tg mice, which could be rescued by PBF depletion. PBF-Tg thyroids exhibited upregulation of Akt and the TSH receptor (TSHR), each known regulators of thyrocyte proliferation, along with upregulation of the downstream proliferative marker cyclin D1. We extended and confirmed findings from the mouse model by examining PBF expression in human multinodular goiters (MNG), a hyperproliferative thyroid disorder, where PBF and TSHR was strongly upregulated relative to normal thyroid tissue. Furthermore, we showed that depleting PBF in human primary thyrocytes was sufficient to increase radioiodine uptake. Together, our findings indicate that overexpression of PBF causes thyroid cell proliferation, macrofollicular lesions, and hyperplasia, as well as repression of the critical therapeutic route for radioiodide uptake.

AB - Pituitary tumor transforming gene (PTTG)-binding factor (PBF or PTTG1IP) is a little characterized protooncogene that has been implicated in the etiology of breast and thyroid tumors. In this study, we created a murine transgenic model to target PBF expression to the thyroid gland (PBF-Tg mice) and found that these mice exhibited normal thyroid function, but a striking enlargement of the thyroid gland associated with hyperplastic and macrofollicular lesions. Expression of the sodium iodide symporter (NIS), a gene essential to the radioiodine ablation of thyroid hyperplasia, neoplasia, and metastasis, was also potently inhibited in PBF-Tg mice. Critically, iodide uptake was repressed in primary thyroid cultures from PBF-Tg mice, which could be rescued by PBF depletion. PBF-Tg thyroids exhibited upregulation of Akt and the TSH receptor (TSHR), each known regulators of thyrocyte proliferation, along with upregulation of the downstream proliferative marker cyclin D1. We extended and confirmed findings from the mouse model by examining PBF expression in human multinodular goiters (MNG), a hyperproliferative thyroid disorder, where PBF and TSHR was strongly upregulated relative to normal thyroid tissue. Furthermore, we showed that depleting PBF in human primary thyrocytes was sufficient to increase radioiodine uptake. Together, our findings indicate that overexpression of PBF causes thyroid cell proliferation, macrofollicular lesions, and hyperplasia, as well as repression of the critical therapeutic route for radioiodide uptake.

UR - http://www.scopus.com/inward/record.url?scp=80053360455&partnerID=8YFLogxK

UR - http://cancerres.aacrjournals.org/content/71/19/6153

U2 - 10.1158/0008-5472.CAN-11-0720

DO - 10.1158/0008-5472.CAN-11-0720

M3 - Article

C2 - 21844185

AN - SCOPUS:80053360455

VL - 71

SP - 6153

EP - 6164

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 19

ER -