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

Oncogene. 2003 Oct 23;22(48):7576-86. doi: 10.1038/sj.onc.1207055.


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 G1 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Division / drug effects
  • Cell Line
  • Cyclin D3
  • Cyclin E
  • Cyclin-Dependent Kinases / metabolism
  • Cyclins / metabolism*
  • Gene Expression Regulation / drug effects
  • Humans
  • Protein Kinases / metabolism
  • Rats
  • Thyroid Diseases / metabolism*
  • Thyroid Diseases / pathology*
  • Thyroid Gland / cytology*
  • Thyroid Gland / drug effects*
  • Thyroid Gland / metabolism
  • Thyroid Gland / pathology
  • Thyrotropin / pharmacology*


  • CCND3 protein, human
  • Ccnd3 protein, rat
  • Cyclin D3
  • Cyclin E
  • Cyclins
  • Thyrotropin
  • Protein Kinases
  • histone H1 kinase
  • Cyclin-Dependent Kinases