Nuclear Hormone Receptors and Transcriptional Regulation

As noted above, nuclear receptor hormones generally act as transcription factors to increase transcription of their target genes. They do this by increasing the rate at which RNA polymerase binds to the target gene's promoter. This occurs in several steps.

The binding of a hormone to the receptor triggers the assembly of other proteins to form a "coactivator complex." The hormone-receptor-coactivator complex binds to a specific DNA sequence (called the hormone response element, a type of transcriptional enhancer). This complex then alters the local DNA structure by directly or indirectly chemically modifying the histones. These modifications open up the DNA, increasing access to the target genes and thereby allowing RNA polymerase and other (general) transcription factors to reach the gene promoter region. Additionally,

RNA polymerase enzyme complex that creates RNA from DNA template promoter DNA

sequence to which RNA polymerase binds to begin transcription histones the proteins around which DNA wind in the chromosome extracellular hormone cell-surface receptor extracellular hormone outside inside

outside inside signal cascade via second messengers

Some hormones trigger second-messenger signal cascades, quickly turning on cellular enzymes for a rapid response.

mRNA messanger RNA

dimerize linkage of two subunits enzymes proteins that control a reaction in a cell the hormone-receptor-coactivator complex can directly interact with general transcription factors to help form a "preinitiation complex" of proteins on the target gene promoter. RNA polymerase then interacts with this complex, and the transcription of the gene into mRNA begins.

All hormone-regulated nuclear receptors activate transcription in this manner. Some, such as the steroid receptors, exist in cells as cytoplasmic complexes with "chaperone proteins," such as HSP90, and are excluded from the nucleus in the absence of the hormone. In the presence of hormone, the complexes dissociate, and the receptors dimerize and are transported to the nucleus, where they activate transcription.

Other receptors, such as the retinoic acid, thyroid hormone, or vitamin D receptors, are always found in the nucleus and interact with their specific target genes in the presence or absence of the hormone. When the hormone is absent, the receptor interacts with "corepressor" proteins. The complex of receptor and corepressor interacts with histone deacetylases, leading to local chromatin condensation and silencing of the target gene. Hormone binding leads to a change in the three-dimensional structure of the receptor, causing dissociation of the corepressor complex and leading to the recruitment of the coactivator complex, which enables the target gene to be transcribed.

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