Hormone response elements gene activation

FIGURE 52-2 There are two modes of hormonal action. (A) Activation of cell-surface receptors and coupled second-messenger systems, with a variety of intracellular consequences. (B) Entry of hormone into the target cell, binding to and activation of an intracellular receptor and binding of the receptor-hormone complex to specific DNA sequences to activate or repress gene expression. DAG, diacylglycerol HRE, hormone-response element. 

An account of the principles which help to understand how hormones achieve their roles in the body is given in Chapter 12. The understanding is based on separation of the effects of hormones into three components the action, the effects (biochemical and physiological) and the function. A steroid hormone binds to a cytosolic intracellular receptor, which then moves into the nucleus where it binds to DNA at a specific site (the steroid response element) and activates genes which result in the formation of proteins that elicit biochemical and physiological effects. This is discussed for cortisol in Chapter 12 and aldosterone in Chapter 22. Much of the interest in the reproductive steroid hormones is in the physiological effects and how these account for their functions. 

B. Binding of ligand activates the receptor so that it can bind specific DNA sequences in regulatory regions of target genes that have hormone-response elements (HREs) (Figure 14—5). 

Model of the interaction of T3 with the T3 receptor. A Inactive phase —the unliganded T3 receptor dimer bound to the thyroid hormone response element (TRE) along with corepressors acts as a suppressor of gene transcription. B Active phase — T3 and T4... 

Regulation of the LDL receptor gene involves a hormone-response element (HRE, see p. 238).] Third, if the cholesterol is not required immediately for some structural or synthetic purpose, it is esterified by acyl CoA cholesterol acyltransferase (ACAT, AC AT transfers a fatty acid from a fatty acyl CoA derivative to cholesterol, producing a cholesteryl ester that can be stored in the cell (Figure 18.21). The activity of ACAT is enhanced in the presence of increased intracellular cholesterol. 

Each steroid hormone diffuses across the plasma membrane of its target cell and binds to a specific cytosolic or nuclear receptor. These receptor-ligand complexes accumulate in the nucleus, dimerize, and bind to specific regulatory DIMA sequences (hormone-response elements) in association with coactivator proteins, thereby causing promoter activation and increased transcription of targeted genes. 

This inability of fully functional receptor complexes to activate a given gene also occurs in normal cells. In new-born chicks, a single injection of oestradiol has a delayed effect on vitellogenin synthesis in liver. Having been exposed once to the hormone, second injections elicit an immediate response. It has been suggested that the first injection demethylates methyl cytosine residues within the hormone response element, thereby allowing receptor attachment [29]. 

The multipUcity of possible combinations of homodimers and heterodimers of RAR and RXR subtypes, and the various possible RXR heterodimers with other receptors, permits a wide variety of active retinoid receptor complexes that bind to different response elements on DNA. Unlike most hormone response elements on DNA, which are palindromic and bind a symmetrical receptor homodimer, the most common type of retinoid response element is a direct repeat purine-G-(G or T)-T-C-A-(Xn)-purine-G-(G or T)-T-C-A, in which the spacer (Xn) is commonly 5 base pairs, but may be 1 or 2. There are also more complex retinoid response elements, including palindromic and inverted palindromic repeats, as well as hexameric motifs with variable spacing. This means that a wide variety of different genes may be regulated differendy in response to retinoids. 

Steroid hormones act by binding to, and activating, nuclear receptors that then bind to hormone response elements on DNA, increasing (or sometimes decreasing) the transcription of specific genes. 

Mammalian nuclear receptors regulate the expression or activation of target genes from promoter sequences that contain either a palindromic or a direct repeat DNA sequence collectively termed hormone response elements (HREs). Most nnclear receptors bind to HREs as either a homodimer... 

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