Abstract
Simple SummaryDevelopment and function of the mammalian brain clearly require precise regulation of gene expression at both the transcriptional and post-transcriptional level. Thyroid hormones have been recognized to play a fundamental role in these processes, by acting at multiple levels and in different brain cell types, through direct effects on transcription, mediated by nuclear receptors, and also by triggering transduction pathways at the plasma membrane. At the same time, due to their effects on proliferation, differentiation, and cell metabolism, thyroid hormones may have a critical role in different kinds of cancer, including brain cancer.The development and maturation of the mammalian brain are regulated by thyroid hormones (THs). Both hypothyroidism and hyperthyroidism cause serious anomalies in the organization and function of the nervous system. Most importantly, brain development is sensitive to TH supply well before the onset of the fetal thyroid function, and thus depends on the trans-placental transfer of maternal THs during pregnancy. Although the mechanism of action of THs mainly involves direct regulation of gene expression (genomic effects), mediated by nuclear receptors (THRs), it is now clear that THs can elicit cell responses also by binding to plasma membrane sites (non-genomic effects). Genomic and non-genomic effects of THs cooperate in modeling chromatin organization and function, thus controlling proliferation, maturation, and metabolism of the nervous system. However, the complex interplay of THs with their targets has also been suggested to impact cancer proliferation as well as metastatic processes. Herein, after discussing the general mechanisms of action of THs and their physiological effects on the nervous system, we will summarize a collection of data showing that thyroid hormone levels might influence cancer proliferation and invasion.
Highlights
It is well known since the end of the 19th century that impaired thyroid function can cause mental retardation and other adult neurological disorders [1,2].the use of sheep thyroid extracts was introduced in 1891 by Murray [2,3] to treat the hypothyroid condition that had been called myxoedema [4]
It was found that deiodinases, selenium-containing enzymes involved in TH metabolism, regulate the levels of active thyroid hormones that are transferred, ensuring TH supply to the fetuses while protecting them from an excess of placental transfer (‘barrier effect’) [11,12,13,14,15,16,17,18,19]
Thyroid hormones have profound effects on many tissues of the body, both during development and in the adult. These effects are mostly triggered by direct regulation of gene expression, mediated by thyroid hormones (THRs), that can bind to chromatin and, depending on the presence of T3 and/or of a variety of regulatory proteins, can cause chromatin structure and gene expression to change
Summary
It is well known since the end of the 19th century that impaired thyroid function can cause mental retardation and other adult neurological disorders [1,2]. The nuclear receptors for thyroid hormones (THRs) can bind to chromatin and, depending on the presence of T3 and/or other regulatory factors, can recruit chromatin remodeling complexes and/or histone-modifying activities, causing the chromatin structure and gene expression to change [31,32,33,34,35,36,37] During their terminal differentiation, cortical neurons acquire a short average spacing of nucleosomes (about 165 bp), while glial cells have a longer nucleosomal length, similar to most other cell types [38,39,40,41]. As mentioned above, the THR ability to enter the nucleus and to bind to DNA and/or to other chromatin proteins depends on post-translational modifications [62,63,64]
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