Steroid receptor-chromatin interactions

DNA methylation is another aspect of chromatin structure which many workers have thought could be involved in steroid-induced gene activation. The onset of expression of certain genes correlates well with specific demethylation but upon hormone withdrawal, when transcription diminishes, the genes remain unmethylated [44], Therefore it is likely that changes in DNA methylation are not directly involved in mediating steroid responses but may arise as a consequence of gene expression. 

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Free steroids that do not bind with plasma proteins enter target cells by passive diffusion and bind with cytoplasmic soluble-binding proteins (acceptor region), forming a steroid-protein complex. This enters the nucleus, where it interacts with steroid receptors on chromatin. 

Steroid receptors control gene expression in target cells. An understanding of the molecular interactions between receptors and specific nuclear components is crucial for elucidating the mechanism of hormone action. Receptor binding to at least three structural elements of nuclei has been described. These include the nuclear matrix, nucleoacidic chromatin proteins (acceptor proteins), and specific DNA sequences in 5 upstream elements of hormone responsive genes. 

Glucocorticoid hormones regulate syntheses of specific mRNA species [14,15]. Interaction of the steroid-receptor complex with highly localized regions of chromatin is essential for this induction, but little of the molecular basis for this activation mechanism is understood. The primary action of glucocortiocoids is very rapid thus, any alterations in chromatin which are essential for this activation would be observed within a few minutes after steroid addition. Also, it is possible that proteins known to be associated with transcriptionally active genes, such as the HMG 14 and 17 [8, 9], are important. 

Whether the steroid hormones enter the cell freely, as assumed by some investigators (O Malley, 1971), or by carrier-mediated transport, it is generally accepted that they bind to receptor proteins in the cytoplasm. The steroid-receptor complex apparently undergoes a thermal activation process which allows the complex to enter the nucleus of the cell, where an incompletely understood interaction with chromatin takes place. As a result, specific DNA sequences are transcribed and the new mRNA is released to the cytoplasm, where corresponding translation results in the formation of protein products typical of the target-tissue response to the hormone (Lippman, 1976). This mechanism of hormone action relies almost exclusively for specificity on the presence and number of cytoplasmic hormone receptors. Sheridan (1975) has... 

Boonyaratanakornkit, V., Melvin, V., Prendergast, P., Altmann, M., Ronfani, L., Bianchi, M.E., Taraseviciene, L., Nordeen, S.K., Allegretto, E.A., and Edwards, D.P. (1998) High-mobility group chromatin proteins 1 and 2 functionally interact with steroid hormone receptors to enhance their DNA binding in vitro and transcriptional activity in mammalian cells. Mol. Cell. Biol. 18, 4471 487. 

Fig. 4.10. Principle of signal transduction by steroid hormone receptors. The steroid hormone receptors in the cytosol are found in the form of an inactive complex with the heat shock proteins Hsp90 and Hsp56 and with protein p23. The binding of the hormone activates the receptor so that it can be transported into the nucleus where it binds to its cognate HRE. It remains unclear in which form the receptor is transported into the nucleus, and to which extent the associated proteins are involved in the transport. One mechanism of activation of transcription initiation involves activation of a histone acetylase and remodehng of chromatin. Furthermore, the receptors interact directly or indirectly with components of the RNA polymerase II holoenzyme (e.g. SUGl).

Nuclear Hormone Receptors. Certain hormones interact directly with hormonal receptors that are located on the chromatin within the cell nucleus (see Fig. 28-2).3 Thyroid hormones (T3 and T4) are a primary example of hormones that bind directly to nuclear receptors.29 After binding, thyroid hormones invoke a series of changes similar to those caused by the steroid-cytosolic receptor complex that is, the nucleus begins to transcribe messenger RNA, which is ultimately translated into specific proteins. In the case of the thyroid hormones, these new proteins usually alter the cell s metabolism. Thyroid hormones are discussed in more detail in Chapter 31. 

All classes of steroid hormones bind to specific cytoplasmic receptors in their respective target tissues, and are then translocated to the nucleus. For example, testosterone, a lipid-soluble substance, enters the cell and is enzymatically reduced to dihydrotestosterone by 5-a reductase. Dihydrotestosterone then becomes bound to a specific androgen receptor site located in the cytoplasm. This complex becomes activated and is then translocated to the nucleus, where it binds to the chromatin acceptor site consisting of DNA and nonhistone chromosomal proteins. This interaction results in the transcription of a specific messenger RNA that is then relocated to the cytoplasm and translated on the cytoplasmic ribosomes, resulting in the synthesis of a new protein that sponsors the androgenic functions (Figure 61.6). 

The general mechanism of receptor-mediated action of steroid hormones is very similar for each of the five classes. Briefly, the steroid enters the cell and binds to an intraceUnar protein. The resnlting receptor-steroid complex is converted in a poorly nn-derstood step called activation to a form that binds to specific, biologically active DNA seqnences (called hormone response elements, or HREs) of the nnclear chromatin. These HRE-bonnd receptor-steroid complexes recrnit various cofactors and then interact with the transcription complex containing RNA polymerase 11 to modify the rates of transcription of a nearby DNA sequence coding for an expressed protein (Fig. 2). This alteration of transcription rate is typically fast (15-30 min) (14). 

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