Critical role of cyclin D3 in TSH-dependent growth of thyrocytes and in hyperproliferative diseases of the thyroid gland.
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.
Dipartimento di Biologia e Patologia Cellulare e Molecolare L.Califano, Università Federico II, via S Pansini 5, 80131 Naples, Italy.
Maria Letizia
ML
Motti
Angelo
A
Boccia
Barbara
B
Belletti
Paola
P
Bruni
Giancarlo
G
Troncone
Letizia
L
Cito
Mario
M
Monaco
Gennaro
G
Chiappetta
Gustavo
G
Baldassarre
Lucio
L
Palombini
Alfredo
A
Fusco
Giuseppe
G
Viglietto
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D056743:Cyclin D3; D019927:Cyclin E; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D013959:Thyroid Diseases / Q000378:metabolism* / Q000473:pathology*; D013961:Thyroid Gland / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013972:Thyrotropin / Q000494:pharmacology*
C534696:CCND3 protein, human; C534698:Ccnd3 protein, rat; D056743:Cyclin D3; D019927:Cyclin E; D016213:Cyclins; D013972:Thyrotropin; D011494:Protein Kinases; C102333:histone H1 kinase; D018844:Cyclin-Dependent Kinases