Thyroid hormone receptors, cell growth and differentiation.
ABSTRACT BACKGROUND: Tissue homeostasis depends on the balance between cell proliferation and differentiation. Thyroid hormones (THs), through binding to their nuclear receptors, can regulate the expression of many genes involved in cell cycle control and cellular differentiation. This can occur by direct transcriptional regulation or by modulation of the activity of different signaling pathways. SCOPE OF REVIEW: In this review we will summarize the role of the different receptor isoforms in growth and maturation of selected tissues and organs. We will focus on mammalian tissues, and therefore we will not address the fundamental role of the THs during amphibian metamorphosis. MAJOR CONCLUSIONS: The actions of THs are highly pleiotropic, affecting many tissues at different developmental stages. As a consequence, their effects on proliferation and differentiation are highly heterogeneous depending on the cell type, the cellular context, and the developmental or transformation status. Both during development and in the adult, stem cells are essential for proper organ formation, maintenance and regeneration. Recent evidence suggests that some of the actions of the thyroid hormone receptors could be secondary to regulation of stem/progenitor cell function. Here we will also include the latest knowledge on the role of these receptors in proliferation and differentiation of embryonic and adult stem cells. GENERAL SIGNIFICANCE: The thyroid hormone receptors are potent regulators of proliferation and differentiation of many cell types. This can explain the important role of the thyroid hormones and their receptors in key processes such as growth, development, tissue homeostasis or cancer. This article is part of a Special Issue entitled Thyroid hormone signalling.
- SourceAvailable from: Ana Franchi[show abstract] [hide abstract]
ABSTRACT: Thyroid hormones are important regulators of cell physiology, inducing cell proliferation, differentiation or apoptosis, depending on the cell type. Thyroid hormones induce proliferation in short-term T lymphocyte cultures. In this study, we assessed the effect of long-term thyroxine (T4) treatment on the balance of proliferation and apoptosis and the intermediate participants in T lymphoma cells. Treatment with T4 affected this balance from the fifth day of culture, inhibiting proliferation in a time-dependent manner. This effect was associated with apoptosis induction, as characterized through nuclear morphological changes, DNA fragmentation, and Annexin V-FITC/Propidium Iodide co-staining. In addition, increased iNOS gene and protein levels, and enzyme activity were observed. The generation of reactive oxygen species, depolarization of the mitochondrial membrane, and a reduction in glutathione levels were also observed. The imbalance between oxidants and antioxidants species is typically associated with the nitration of proteins, including PKCζ, an isoenzyme essential for lymphoma cell division and survival. Consistently, evidence of PKCζ nitration via proteasome degradation was also observed in this study. Taken together, these results suggest that the long-term culture of T lymphoma cells with T4 induces apoptosis through the increased production of oxidative species resulting from both augmented iNOS activity and the loss of mitochondrial function. These species induce the nitration of proteins involved in cell viability, promoting proteasome degradation. Furthermore, we discuss the impact of these results on the modulation of T lymphoma growth and the thyroid status in vivo.Apoptosis 06/2013; · 4.07 Impact Factor