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TGF-beta1 actions on FRTL-5 cells provide a model for the physiological regulation of thyroid growth
C Carneiro1, C V Alvarez, J Zalvide
1Departamento de Fisiología, Laboratorio de Neurociencia Ramón Domínguez, Santiago de Compostela, Spain.
Abstract:
Little is known about the TGF-beta1 mechanism that promotes thyroid cell growth arrest. We assessed TGF-beta1 effects on Fisher rat thyroid cell line (FRTL-5). This allowed us to study TGF-beta1 action on thyroid cells in various physiological situations such as actively proliferating cells, resting cells stimulated to proliferate by the action of various mitogens, and resting cells. TGF-beta1 arrested proliferating FRTL-5 cells, increasing c-myc mRNA levels and reducing p27-free cyclin D1 protein levels, without affecting either the cellular content of p27 or the cyclin D1-p27 complexes. Moreover, TGF-beta1 treatment reduced the activity of cyclin E-CDK2 complexes and, consequently, pRB was found to be hypophosphorylated. TGF-beta1 prevented resting cells to enter in the cell cycle when stimulated with growing medium (newborn calf serum plus a mixture of five hormones) but not when TSH (thyroid stimulating hormone) plus IGF-1 (Insulin-like growth factor I) were used as mitogens. Both stimuli increased the levels of cyclins D1, D3 and E but TGF-beta1 had a greater effect in decreasing these cyclin levels in growing-medium stimulated cells than in TSH + IGF-1. This suggests that for FRTL-5 cells, the content of these cyclins must exceed a threshold to progress through the cell cycle. TGF-beta1 induced apoptosis in quiescent cells, accompanied by a reduction in p27 protein levels and an increase in c-myc expression. Interestingly, TGF-beta1-induced variations in prothymosin alpha and c-myc mRNA levels were not correlated. TGF-beta1 always promoted an increase of p15 mRNA levels. In summary, our results point to the fact that TGF-beta1 could play a physiological role in the control of thyroid growth through the modification of cell cycle regulatory proteins.
Insights
Transforming growth factor-beta1 (TGF-beta1) halts thyroid cell proliferation by altering cell cycle proteins. It also induces apoptosis in resting cells, suggesting a role in thyroid growth control.
Area of Science:
- Endocrinology
- Cell Biology
- Molecular Biology
Background:
- The precise mechanisms by which transforming growth factor-beta1 (TGF-beta1) induces thyroid cell growth arrest remain incompletely understood.
- Investigating TGF-beta1's role in thyroid cell cycle regulation is crucial for understanding thyroid homeostasis.
Purpose of the Study:
- To elucidate the specific molecular mechanisms underlying TGF-beta1-mediated growth arrest in thyroid cells.
- To examine the effects of TGF-beta1 on thyroid cell proliferation, cell cycle progression, and apoptosis under various physiological conditions.
Main Methods:
- Utilized the Fisher rat thyroid cell line (FRTL-5) to model thyroid cell behavior.
- Assessed the impact of TGF-beta1 on actively proliferating, mitogen-stimulated resting, and quiescent FRTL-5 cells.
- Analyzed key cell cycle regulatory proteins, including cyclins, cyclin-dependent kinase inhibitors, and transcription factors (e.g., c-myc).
Main Results:
- TGF-beta1 arrested proliferating cells by increasing c-myc mRNA and decreasing p27-free cyclin D1, leading to hypophosphorylated pRB.
- TGF-beta1 inhibited resting cells from entering the cell cycle in response to standard growth media but not TSH + IGF-1.
- TGF-beta1 induced apoptosis in quiescent cells, correlating with reduced p27 and increased c-myc, and consistently elevated p15 mRNA levels.
Conclusions:
- TGF-beta1 significantly impacts thyroid cell cycle progression and viability.
- The findings suggest TGF-beta1 plays a physiological role in regulating thyroid growth via modulation of cell cycle proteins.