Critical role of cyclin D3 in TSH-dependent growth of thyrocytes and in hyperproliferative diseases of the thyroid gland

Maria Letizia Motti, Angelo Boccia, Barbara Belletti, Paola Bruni, Giancarlo Troncone, Letizia Cito, Mario Monaco, Gennaro Chiappetta, Gustavo Baldassarre, Lucio Palombini, Alfredo Fusco, Giuseppe Viglietto

Research output: Contribution to journalArticlepeer-review

Abstract

We report that cyclin D3 is rate limiting for G1 progression in thyroid follicular cells and that its constitutive upregulation by chronic stimulation of the TSH/cAMP pathway plays a role in human and experimental hyperproliferative diseases of the thyroid gland. These conclusions are supported by in vitro and in vivo studies. In rat thyrocytes (PC Cl 3 cells), cyclin D3 expression is enhanced in response to activation of the TSH/cAMP pathway. Interference with the expression of G1 cyclins (in particular cyclin D3) by the antisense methodology strongly reduced TSH-dependent proliferation of PC Cl 3 cells, indicating that proper progression through G4 requires cyclin D3. Accordingly, PC Cl 3 cells engineered to overexpress cyclin D3 (PC-D3 cells) show enhanced growth rate and elude hormone-dependence and contact inhibition. Using an animal experimental model of thyroid stimulation, we demonstrate that cyclin D3 is a key mediator of TSH-dependent proliferation of thyroid follicular cells also in vivo. Cyclin D3 protein levels were higher in the thyrocytes from glands of propylthiouracil-treated rats compared with control animals. The increase in cyclin D3 expression occurred after the propylthiouracil-induced increase in TSH levels and preceded the burst of cell proliferation. Finally, we found that cyclin D3 protein is expressed in a fraction of human goiters but it is strongly overexpressed in most follicular adenomas.

Original languageEnglish
Pages (from-to)7576-7586
Number of pages11
JournalOncogene
Volume22
Issue number48
DOIs
Publication statusPublished - Oct 23 2003

Keywords

  • Cyclin D3
  • p27
  • Thyroid
  • TSH

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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