Regulation of Pituitary Tumor Transforming Gene (PTTG) expression and phosphorylation in thyroid cells

Gregory D Lewy; Gavin A Ryan; Martin L Read; Jim C W Fong; Vikki Poole; Robert I Seed; Neil Sharma; Vicki E Smith; Perkin P K Kwan; Sarah L Stewart; Andrea Bacon; Adrian Warfield; Jayne A Franklyn; Christopher J McCabe; Kristien Boelaert

doi:10.1210/en.2012-2156

Regulation of Pituitary Tumor Transforming Gene (PTTG) expression and phosphorylation in thyroid cells

Gregory D Lewy, Gavin A Ryan, Martin L Read, Jim C W Fong, Vikki Poole, Robert I Seed, Neil Sharma, Vicki E Smith, Perkin P K Kwan, Sarah L Stewart, Andrea Bacon, Adrian Warfield, Jayne A Franklyn, Christopher J McCabe, Kristien Boelaert

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Abstract

Human Pituitary Tumor Transforming Gene (hPTTG) is a multifunctional proto-oncogene implicated in the initiation and progression of several tumors. Phosphorylation of hPTTG is mediated by cyclin-dependent kinase 2 (CDC2), whilst cellular expression is regulated by specificity protein 1 (SP1). The mechanisms underlying hPTTG propagation of aberrant thyroid cell growth have not been fully defined. We set out to investigate the interplay between hPTTG and growth factors, as well as the effects of phosphorylation and SP1 regulation on hPTTG expression and function. In our study, epidermal growth factor (EGF), transforming growth factor alpha (TGFα) and insulin-like growth factor 1 (IGF-1) induced hPTTG expression and phosphorylation in thyroid cells, which was associated with activation of mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K). Growth factors induced hPTTG independently of CDC2 and SP1 in thyroid carcinoma cells. Strikingly, CDC2 depletion in TPC-1 cells resulted in enhanced expression and phosphorylation of hPTTG and reduced cellular proliferation. In reciprocal experiments, hPTTG over-expression induced EGF, IGF-1 and TGFα mRNAs in primary human thyrocytes. Treatment of primary human thyrocytes with conditioned media derived from hPTTG transfected cells resulted in autocrine upregulation of hPTTG protein, which was ameliorated by growth factor depletion or growth factor receptor tyrosine kinase inhibitors. A transgenic murine model of thyroid targeted hPTTG over-expression (hPTTG-Tg) (FVB/N strain, both sexes) demonstrated smaller thyroids with reduced cellular proliferation and enhanced secretion of Egf. In contrast, Pttg(-/-) knockout mice (c57bl6 strain, both sexes) showed reduced thyroidal Egf mRNA expression. These results define hPTTG as having a central role in thyroid autocrine signalling mechanisms via growth factors, with profound implications for promotion of transformed cell growth.

Original language	English
Journal	Endocrinology
Early online date	18 Jul 2013
DOIs	https://doi.org/10.1210/en.2012-2156
Publication status	Published - 18 Jul 2013

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10.1210/en.2012-2156

Novel binding partners of PBF in Thyroid Tumourgenesis
Sharma, N. & McCabe, C.
Medical Research Council
1/09/10 → 31/08/13
Project: Research Councils

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Lewy, G. D., Ryan, G. A., Read, M. L., Fong, J. C. W., Poole, V., Seed, R. I., Sharma, N., Smith, V. E., Kwan, P. P. K., Stewart, S. L., Bacon, A., Warfield, A., Franklyn, J. A., McCabe, C. J., & Boelaert, K. (2013). Regulation of Pituitary Tumor Transforming Gene (PTTG) expression and phosphorylation in thyroid cells. Endocrinology. Advance online publication. https://doi.org/10.1210/en.2012-2156

@article{73ecccba3e1042e0b8972a4608149e41,

title = "Regulation of Pituitary Tumor Transforming Gene (PTTG) expression and phosphorylation in thyroid cells",

abstract = "Human Pituitary Tumor Transforming Gene (hPTTG) is a multifunctional proto-oncogene implicated in the initiation and progression of several tumors. Phosphorylation of hPTTG is mediated by cyclin-dependent kinase 2 (CDC2), whilst cellular expression is regulated by specificity protein 1 (SP1). The mechanisms underlying hPTTG propagation of aberrant thyroid cell growth have not been fully defined. We set out to investigate the interplay between hPTTG and growth factors, as well as the effects of phosphorylation and SP1 regulation on hPTTG expression and function. In our study, epidermal growth factor (EGF), transforming growth factor alpha (TGFα) and insulin-like growth factor 1 (IGF-1) induced hPTTG expression and phosphorylation in thyroid cells, which was associated with activation of mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K). Growth factors induced hPTTG independently of CDC2 and SP1 in thyroid carcinoma cells. Strikingly, CDC2 depletion in TPC-1 cells resulted in enhanced expression and phosphorylation of hPTTG and reduced cellular proliferation. In reciprocal experiments, hPTTG over-expression induced EGF, IGF-1 and TGFα mRNAs in primary human thyrocytes. Treatment of primary human thyrocytes with conditioned media derived from hPTTG transfected cells resulted in autocrine upregulation of hPTTG protein, which was ameliorated by growth factor depletion or growth factor receptor tyrosine kinase inhibitors. A transgenic murine model of thyroid targeted hPTTG over-expression (hPTTG-Tg) (FVB/N strain, both sexes) demonstrated smaller thyroids with reduced cellular proliferation and enhanced secretion of Egf. In contrast, Pttg(-/-) knockout mice (c57bl6 strain, both sexes) showed reduced thyroidal Egf mRNA expression. These results define hPTTG as having a central role in thyroid autocrine signalling mechanisms via growth factors, with profound implications for promotion of transformed cell growth.",

author = "Lewy, {Gregory D} and Ryan, {Gavin A} and Read, {Martin L} and Fong, {Jim C W} and Vikki Poole and Seed, {Robert I} and Neil Sharma and Smith, {Vicki E} and Kwan, {Perkin P K} and Stewart, {Sarah L} and Andrea Bacon and Adrian Warfield and Franklyn, {Jayne A} and McCabe, {Christopher J} and Kristien Boelaert",

year = "2013",

month = jul,

day = "18",

doi = "10.1210/en.2012-2156",

language = "English",

journal = "Endocrinology",

issn = "0013-7227",

publisher = "Endocrine Society",

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T1 - Regulation of Pituitary Tumor Transforming Gene (PTTG) expression and phosphorylation in thyroid cells

AU - Lewy, Gregory D

AU - Ryan, Gavin A

AU - Read, Martin L

AU - Fong, Jim C W

AU - Poole, Vikki

AU - Seed, Robert I

AU - Sharma, Neil

AU - Smith, Vicki E

AU - Kwan, Perkin P K

AU - Stewart, Sarah L

AU - Bacon, Andrea

AU - Warfield, Adrian

AU - Franklyn, Jayne A

AU - McCabe, Christopher J

AU - Boelaert, Kristien

PY - 2013/7/18

Y1 - 2013/7/18

N2 - Human Pituitary Tumor Transforming Gene (hPTTG) is a multifunctional proto-oncogene implicated in the initiation and progression of several tumors. Phosphorylation of hPTTG is mediated by cyclin-dependent kinase 2 (CDC2), whilst cellular expression is regulated by specificity protein 1 (SP1). The mechanisms underlying hPTTG propagation of aberrant thyroid cell growth have not been fully defined. We set out to investigate the interplay between hPTTG and growth factors, as well as the effects of phosphorylation and SP1 regulation on hPTTG expression and function. In our study, epidermal growth factor (EGF), transforming growth factor alpha (TGFα) and insulin-like growth factor 1 (IGF-1) induced hPTTG expression and phosphorylation in thyroid cells, which was associated with activation of mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K). Growth factors induced hPTTG independently of CDC2 and SP1 in thyroid carcinoma cells. Strikingly, CDC2 depletion in TPC-1 cells resulted in enhanced expression and phosphorylation of hPTTG and reduced cellular proliferation. In reciprocal experiments, hPTTG over-expression induced EGF, IGF-1 and TGFα mRNAs in primary human thyrocytes. Treatment of primary human thyrocytes with conditioned media derived from hPTTG transfected cells resulted in autocrine upregulation of hPTTG protein, which was ameliorated by growth factor depletion or growth factor receptor tyrosine kinase inhibitors. A transgenic murine model of thyroid targeted hPTTG over-expression (hPTTG-Tg) (FVB/N strain, both sexes) demonstrated smaller thyroids with reduced cellular proliferation and enhanced secretion of Egf. In contrast, Pttg(-/-) knockout mice (c57bl6 strain, both sexes) showed reduced thyroidal Egf mRNA expression. These results define hPTTG as having a central role in thyroid autocrine signalling mechanisms via growth factors, with profound implications for promotion of transformed cell growth.

AB - Human Pituitary Tumor Transforming Gene (hPTTG) is a multifunctional proto-oncogene implicated in the initiation and progression of several tumors. Phosphorylation of hPTTG is mediated by cyclin-dependent kinase 2 (CDC2), whilst cellular expression is regulated by specificity protein 1 (SP1). The mechanisms underlying hPTTG propagation of aberrant thyroid cell growth have not been fully defined. We set out to investigate the interplay between hPTTG and growth factors, as well as the effects of phosphorylation and SP1 regulation on hPTTG expression and function. In our study, epidermal growth factor (EGF), transforming growth factor alpha (TGFα) and insulin-like growth factor 1 (IGF-1) induced hPTTG expression and phosphorylation in thyroid cells, which was associated with activation of mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K). Growth factors induced hPTTG independently of CDC2 and SP1 in thyroid carcinoma cells. Strikingly, CDC2 depletion in TPC-1 cells resulted in enhanced expression and phosphorylation of hPTTG and reduced cellular proliferation. In reciprocal experiments, hPTTG over-expression induced EGF, IGF-1 and TGFα mRNAs in primary human thyrocytes. Treatment of primary human thyrocytes with conditioned media derived from hPTTG transfected cells resulted in autocrine upregulation of hPTTG protein, which was ameliorated by growth factor depletion or growth factor receptor tyrosine kinase inhibitors. A transgenic murine model of thyroid targeted hPTTG over-expression (hPTTG-Tg) (FVB/N strain, both sexes) demonstrated smaller thyroids with reduced cellular proliferation and enhanced secretion of Egf. In contrast, Pttg(-/-) knockout mice (c57bl6 strain, both sexes) showed reduced thyroidal Egf mRNA expression. These results define hPTTG as having a central role in thyroid autocrine signalling mechanisms via growth factors, with profound implications for promotion of transformed cell growth.

U2 - 10.1210/en.2012-2156

DO - 10.1210/en.2012-2156

M3 - Article

C2 - 23867215

SN - 0013-7227

JO - Endocrinology

JF - Endocrinology

ER -

Regulation of Pituitary Tumor Transforming Gene (PTTG) expression and phosphorylation in thyroid cells

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Novel binding partners of PBF in Thyroid Tumourgenesis

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