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This version published online on May 27, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0104
A more recent version of this article appeared on September 1, 2004
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Submitted on March 10, 2004
Accepted on May 21, 2004

TSH and serum regulate thyroid cell proliferation through differential effects on p27 expression and localization

Aurélia E. Lewis, Aphrothiti J. Fikaris, Gregory V. Prendergast, and Judy L. Meinkoth*

Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

* To whom correspondence should be addressed. E-mail: Meinkoth{at}pharm.med.upenn.edu.

Thyroid cell proliferation is regulated by the concerted action of thyrotropin/cAMP and serum growth factors. The specific contributions of cAMP-dependent vs. -independent signals to cell cycle progression are not well understood. We examined the molecular basis for the synergistic effects of thyrotropin and serum on G1/S phase cell cycle progression in rat thyroid cells. Although strictly required for thyroid cell proliferation, thyrotropin failed to stimulate G1 phase cell cycle progression. Together with serum, thyrotropin increased the number of cycling cells. thyrotropin enhanced the effects of serum on Rb hyperphosphorylation, CDK-2 activity and cyclin A expression. Most notably, thyrotropin and serum elicited strikingly different effects on p27 localization. thyrotropin stimulated the nuclear accumulation of p27, while serum induced its nuclear export. Unexpectedly, thyrotropin enhanced the depletion of nuclear p27 in serum-treated cells. Furthermore, only combined treatment with thyrotropin and serum led to rapamycin-sensitive p27 turnover. Together thyrotropin and serum stimulated p70S6K activity that remained high through S phase. These data suggest that thyrotropin regulates cell cycle progression in part by increasing the number of cycling cells through p70S6K-mediated effects on the localization of p27.
Key words: TSH • cAMP • cell cycle progression • p27




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