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), 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), TGFα, 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 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 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.
authors.affiliation: FRCP, PhD, Senior Clinical Lecturer and Honorary Consultant Physician, Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TH, United Kingdom. k.boelaert@bham.ac.uk.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Lewy
authors.forename: Gavin A
authors.initials: GA
authors.lastname: Ryan
authors.forename: Martin L
authors.initials: ML
authors.lastname: Read
authors.forename: Jim C W
authors.initials: JC
authors.lastname: Fong
authors.forename: Vikki
authors.initials: V
authors.lastname: Poole
authors.forename: Robert I
authors.initials: RI
authors.lastname: Seed
authors.forename: Neil
authors.initials: N
authors.lastname: Sharma
authors.forename: Vicki E
authors.initials: VE
authors.lastname: Smith
authors.forename: Perkin P K
authors.initials: PP
authors.lastname: Kwan
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Stewart
authors.forename: Andrea
authors.initials: A
authors.lastname: Bacon
authors.forename: Adrian
authors.initials: A
authors.lastname: Warfield
authors.forename: Jayne A
authors.initials: JA
authors.lastname: Franklyn
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: McCabe
authors.forename: Kristien
authors.initials: K
authors.lastname: Boelaert
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D006224:Cricetinae; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019899:Paracrine Communication; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D064249:Securin / Q000235:genetics / Q000378:metabolism*; D013961:Thyroid Gland / Q000166:cytology*
chemical_list: D007136:Immunoglobulins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C090698:SP1 antigen; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human; D004815:Epidermal Growth Factor; D016203:CDC2 Protein Kinase