Mechanism of Hormone Action: Direct Gene Activation

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The lipid-soluble hormones, steroids and thyroid hormone bind to receptors typically located inside cells. Most of these intracellular receptors are located in the nucleus. Each receptor has two binding sites: One site binds the hormone. One site binds to DNA. In the absence of hormone, the receptors bound to a chaperone protein that masks the DNA binding site and probably also acts to stabilize the protein. The receptors are not active until a hormone binds to them. When a hormone binds to a receptor, the receptor changes shape. This activates the receptor and causes the chaperone to dissociate from it. If it not already in the nucleus, the hormone receptor complex enters the nucleus. Hormone receptor complexes act as transcription factors. They bind to specific regions of DNA called hormone response elements. Typically, the binding results in activation of, or turning on, a particular gene. When a gene is activated, messenger RNA, mRNA, is produced and enters the cytosol where it is translated to form proteins Typically, the proteins that are synthesized are enzymes that catalyze biochemical reactions and cause the response of the cell. The properties of transcription factors are far more complex than what has been described thus far. Transcription factors can regulate more than one gene and they can also decrease, or turn off, the activity of genes. Transcription factors for different hormones can bind to the same hormone response elements, although each transcription factor activates a specific group of genes. Now we will study the mechanism used by cortisol and thyroid hormone to induce cellular responses. The action of cortisol follows the typical pattern for steroid hormones. It binds to glucocorticoid receptors that are present in nearly all cells. Some of the many cellular responses to cortisol are: Gluconeogenesis, glycogenolysis Lipolysis and protein breakdown Enhances vasoconstriction Inhibits inflammation and immune response. Cortisol acts to maintain high levels of fuel molecules, maintain blood pressure, and modulate body defenses, all necessary for the stress response. We will study the stress response in another topic. The thyroid hormones T3 and T4 enter cells by diffusion and to some extent by carrier mediated transport. Once inside, T4 is converted to T3, the active form of the hormone. Receptors for thyroid hormones differ from steroid hormone receptors. They are bound to the response elements of the DNA. T3 binds to the receptor causing gene activation or eliminating the inhibition that was present, thus allowing genes to be expressed. Small amounts of T4 may also bind to the receptors. Receptors for thyroid hormones are also found in cytosol and mitochondria, but their function is poorly understood. Nearly all body cells have thyroid hormone receptors and require thyroid hormone for normal function. Here are some of the many effects of thyroid hormone: Raises basal metabolic rate Alters carbohydrate, lipid and protein metabolism Essential for growth Essential for nervous system development and function. Thyroid hormone is the main regulator of metabolic rate in the body.