Regulation of Pituitary Tumor Transforming Gene (PTTG) Expression and Phosphorylation in Thyroid Cells

被引:16
作者
Lewy, Gregory D. [1 ]
Ryan, Gavin A. [1 ]
Read, Martin L. [1 ]
Fong, Jim C. W. [1 ]
Poole, Vikki [1 ]
Seed, Robert I. [1 ]
Sharma, Neil [1 ]
Smith, Vicki E. [1 ]
Kwan, Perkin P. K. [1 ]
Stewart, Sarah L. [1 ]
Bacon, Andrea [2 ]
Warfield, Adrian [3 ]
Franklyn, Jayne A. [1 ]
McCabe, Christopher J. [1 ]
Boelaert, Kristien [1 ]
机构
[1] Univ Birmingham, Sch Clin & Expt Med, Inst Biomed Res, Birmingham B15 2TH, W Midlands, England
[2] Univ Birmingham, Biomed Serv Unit, Birmingham B15 2TT, W Midlands, England
[3] Univ Hosp Birmingham Natl Hlth Serv Fdn Trust, Birmingham B15 2TJ, W Midlands, England
基金
英国医学研究理事会;
关键词
ENDOTHELIAL GROWTH-FACTOR; MOUSE MODEL; CHROMATID SEPARATION; CAUSES ANEUPLOIDY; PROTEIN; INSULIN; SECURIN; MICE; IDENTIFICATION; HYPERPLASIA;
D O I
10.1210/en.2012-2156
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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), whereas 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), TGF alpha, and IGF-1 induced hPTTG expression and phosphorylation in thyroid cells, which was associated with activation of MAPK and phosphoinositide 3-kinase. 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 overexpression induced EGF, IGF-1, and TGF alpha 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 overexpression (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 signaling mechanisms via growth factors, with profound implications for promotion of transformed cell growth.
引用
收藏
页码:4408 / 4422
页数:15
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