Regulation of Thyroid Cell Proliferation by TSH and Other Factors: A Critical Evaluation of in Vitro Models
Takao Kimura,
Alexandra Van Keymeulen,
Jacqueline Golstein,
Alfredo Fusco,
Jacques E. Dumont and
Pierre P. Roger
Institute of Interdisciplinary Research (IRIBHN) (T.K., A.V.K.,
J.G., J.E.D., P.P.R.), School of Medicine, Université Libre de
Bruxelles, Campus Erasme, B-1070 Brussels, Belgium; and Dipartimento di
Biologia e Pathologia Cellulare e Moleculare (A.F.), Facoltà di
Medicina e Chirurgia di Napoli, Università degli Studi di Napoli,
I-80131 Napoli, Italy
Correspondence: Address all correspondence and requests for reprints to: Dr. J. E. Dumont or Dr. P. Roger at IRIBHN, Faculté de Médecine, Campus Erasme, 808 route de Lennik, B-1070 Bruxelles, Belgium, E-mail: proger@ulb.ac.be and jedumont{at}ulb.ac.be
TSH via cAMP, and various growth factors, in cooperation with
insulinor IGF-I stimulate cell cycle progression and proliferationin
various thyrocyte culture systems, including rat thyroidcell lines
(FRTL-5, WRT, PC Cl3) and primary cultures of rat,dog, sheep and human
thyroid. The available data on cell signalingcascades, cell cycle
kinetics, and cell cycle-regulatory proteinsare thoroughly and
critically reviewed in these experimentalsystems. In most FRTL-5
cells, TSH (cAMP) merely acts as a priming/competencefactor amplifying
PI3K and MAPK pathway activation and DNA synthesiselicited by
insulin/IGF-I. In WRT cells, TSH and insulin/IGF-Ican independently
activate Ras and PI3K pathways and DNA synthesis.In dog thyroid
primary cultures, TSH (cAMP) does not activateRas and PI3K, and cAMP
must be continuously elevated by TSHto directly control the
progression through G1 phase. This effectis exerted, at
least in part, via the cAMP-dependent activationof the required cyclin
D3, itself synthesized in response toinsulin/IGF-I. This and other
discrepancies show that the mechanisticlogics of cell cycle
stimulation by cAMP profoundly divergein these different in
vitro models of the same cell. Therefore,although these
different thyrocyte systems constitute interestingmodels of the wide
diversity of possible mechanisms of cAMP-dependentproliferation in
various cell types, extrapolation of in vitro
mechanisticdata to TSH-dependent goitrogenesis in man can only be
acceptedin the cases where independent validation is
provided.
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J. E. Dumont, S. Dremier, I. Pirson, and C. Maenhaut Cross signaling, cell specificity, and physiology
Am J Physiol Cell Physiol,
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[Abstract][Full Text][PDF]
