The proliferative status of thyrotropes is dependent on modulation of specific cell cycle regulators by thyroid hormone.
In this report we have examined changes in cell growth parameters, cell cycle effectors, and signaling pathways that accompany thyrotrope growth arrest by thyroid hormone (TH) and growth resumption after its withdrawal. Flow cytometry and immunohistochemistry of proliferation markers demonstrated that TH treatment of thyrotrope tumors resulted in a reduction in the fraction of cells in S-phase that is restored upon TH withdrawal. This is accompanied by dephosphorylation and rephosphorylation of retinoblastoma (Rb) protein. The expression levels of cyclin-dependent kinase 2 and cyclin A, as well as cyclin-dependent kinase 1 and cyclin B, were decreased by TH, and after withdrawal not only did these regulators of Rb phosphorylation and mitosis increase in their expression but so too did the D1 and D3 cyclins. We also noted a rapid induction and subsequent disappearance of the type 5 receptor for the growth inhibitor somatostatin with TH treatment and withdrawal, respectively. Because somatostatin can arrest growth by activating MAPK pathways, we examined these pathways in TtT-97 tumors and found that the ERK pathway and several of its upstream and downstream effectors, including cAMP response element binding protein, were activated with TH treatment and deactivated after its withdrawal. This led to the hypothesis that TH, acting through increased type 5 somatostatin receptor, could activate the ERK pathway leading to cAMP response element binding protein-dependent decreased expression of critical cell cycle proteins, specifically cyclin A, resulting in hypophosphorylation of Rb and its subsequent arrest of S-phase progression. These processes are reversed when TH is withdrawn, resulting in an increase in the fraction of S-phase cells.
Woodmansee
Whitney W
WW
Division of Endocrinology, Metabolism, and Diabetes, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80045, USA.
Kerr
Janice M
JM
Tucker
Elizabeth A
EA
Mitchell
Jeffrey R
JR
Haakinson
Danielle J
DJ
Gordon
David F
DF
Ridgway
E Chester
EC
Wood
William M
WM
D000818:Animals; D004195:Disease Models, Animal; D007037:Hypothyroidism / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D013961:Thyroid Gland / Q000166:cytology* / Q000187:drug effects; D013963:Thyroid Hormones / Q000494:pharmacology*; D013965:Thyroidectomy; D013972:Thyrotropin / Q000235:genetics / Q000494:pharmacology
D018809:Proliferating Cell Nuclear Antigen; D013963:Thyroid Hormones; D013972:Thyrotropin; D020929:Mitogen-Activated Protein Kinase Kinases