8 Регуляция экспрессии генов. Система передачи сигнала (1160077), страница 4
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The DNAbinding region is highly conserved. The sequenceshown here (see Table 5-1 for amino acid abbreviations) is that for the estrogen receptor, but the residues in bold type are common to all such receptors.Eight critical Cys residues bind to two Zn2+ ionsthat stabilize the "zinc finger" structure sharedwith many other DNA-binding proteins (see Fig.27—12). The regulation of gene expression is described in more detail in Chapter 27.CH3TamoxifenCHc=C—CH 3RU486(mifepristone)782Part III Bioenergetics and MetabolismIn addition to the DNA-binding and ligand-binding regions, steroidreceptors also have two domains that interact (in a way not fully understood) with elements of the transcriptional (RNA-synthesizing)machinery in the nucleus.
The combination of DNA binding and thisinteraction with the transcriptional apparatus allows the steroid hormone-receptor complex to modulate the rate at which proteins areproduced from a specific gene. The relatively slow action of steroidhormones (hours or days are required for their full effect) is a consequence of their mode of action; time is required for RNA synthesis inthe nucleus and for the subsequent protein synthesis.SummaryIn mammals there is a division of metabolic laboramong specialized tissues and organs. Coordination of the body's diverse metabolic activities isaccomplished by hormonal signals that circulate inthe blood.
The liver is the central distributing andprocessing organ for nutrients. Sugars and aminoacids produced in digestion cross the intestinal epithelium and enter the blood, which carries them tothe liver. Some triacylglycerols derived from ingested lipids also make their way to the liver,where the constituent fatty acids are used in a variety of processes. Glucose-6-phosphate is the keyintermediate in carbohydrate metabolism.
It maybe polymerized into glycogen, dephosphorylated toblood glucose, or converted to fatty acids via acetylCoA. It may undergo degradation by glycolysis andthe citric acid cycle to yield ATP energy or by thepentose phosphate pathway to yield pentoses andNADPH. Amino acids are used to synthesize liverand plasma proteins, or their carbon skeletonsmay be converted into glucose and glycogen by gluconeogenesis; the ammonia formed by their deamination is converted into urea. Fatty acids may beconverted by the liver into other triacylglycerols,cholesterol, or plasma lipoproteins for transport toand storage in adipose tissue.
They may also beoxidized to yield ATP, and to form ketone bodies tobe circulated to other tissues.Skeletal muscle is specialized to produce ATPfor mechanical work. During strenuous muscularactivity, glycogen is the ultimate fuel and is fermented into lactate, supplying ATP. During recovery the lactate is reconverted (through gluconeogenesis) to glycogen and glucose in the liver.Phosphocreatine is an immediate source of ATPduring active contraction. Heart muscle obtains allof its ATP from oxidative phosphorylation. Thebrain uses only glucose and /3-hydroxybutyrate asfuels, the latter being important during fasting orstarvation. The brain uses most of its ATP energyfor the active transport of Na + and K" and themaintenance of the electrical potential of neuronalmembranes.
The blood links all of the organs, carrying nutrients, waste products, and hormonal signals between them.Hormones are chemical messengers (peptides,amines, or steroids) secreted by certain tissues intothe blood, serving to regulate the activity of othertissues. They act in a hierarchy of functions. Nerveimpulses stimulate the hypothalamus to send specific hormones to the pituitary gland, stimulating(or inhibiting) the release of tropic hormones. Theanterior pituitary hormones in turn stimulateother endocrine glands (thyroid, adrenals, pancreas) to secrete their characteristic hormones,which in turn stimulate specific target tissues.The concentration of glucose in the blood is hormonally regulated.
Fluctuations in blood glucose(which is normally about 80 mg/100 mL or 4.5 DIM)due to dietary uptake or vigorous exercise arecounterbalanced by a variety of hormonally triggered changes in the metabolism of several organs.Epinephrine prepares the body for increased activity by mobilizing blood glucose from glycogen andother precursors. Low blood glucose results in therelease of glucagon, which stimulates glucose release from liver glycogen and shifts the fuel metabolism in liver and muscle to fatty acids, sparingglucose for use by the brain. In prolonged fasting,triacylglycerols become the principal fuels; theliver converts the fatty acids to ketone bodies forexport to other tissues, including the brain. Highblood glucose elicits the release of insulin, whichspeeds the uptake of glucose by tissues and favorsthe storage of fuels as glycogen and triacylglycerols. In untreated diabetes, insulin is either not produced or is not recognized by the tissues, and theutilization of blood glucose is compromised.
Whenblood glucose levels are high, glucose is excretedintact into the urine. Tissues then depend uponfatty acids for fuel (producing ketone bodies) anddegrade cellular proteins to make glucose fromChapter 22 Integration and Hormonal Regulation of Mammalian Metabolism783their glucogenic amino acids. Untreated diabetes ischaracterized by high glucose levels in the bloodand urine and the production and excretion of ketone bodies.Hormones act through a small number of fundamentally similar mechanisms. Epinephrine bindsto specific /3-adrenergic receptors on the outer faceof hepatocytes and myocytes.
A stimulatory GTPbinding protein (Gs) mediates between the adrenergic receptor and adenylate cyclase on the innerface of the plasma membrane. When the adrenergic receptor is occupied, adenylate cyclase is activated and converts ATP to cAMP (the second messenger), which then activates the cAMP-dependentprotein kinase. This protein kinase phosphorylatesand activates inactive phosphorylase b kinase,which in a subsequent step phosphorylates andactivates glycogen phosphorylase. Cyclic nucleotide phosphodiesterase terminates the signal byconverting cAMP to AMP.
The cAMP-dependentprotein kinase also phosphorylates and regulates anumber of other enzymes present in target tissues.(Glucagon acts by an essentially similar mechanism except that the tissue distribution of glucagon receptors is different; this hormone acts primarily on the liver.) This cascade of events, inwhich a single molecule of hormone activates a catalyst that in turn activates another catalyst and soon, results in large signal amplification; this ischaracteristic of all hormone-activated systems.Cyclic GMP acts as the second messenger for otherhormones, by a similar mechanism.Protein phosphorylation is a universal mechanism for rapid and reversible enzyme regulation.To reverse the effects of signal-stimulated proteinkinases, cells contain a variety of phosphatases.These enzymes, too, are subject to regulation byextracellular and intracellular signals.The insulin receptor represents a second signaltransducing mechanism.
The receptor is an integral protein of the plasma membrane. Binding ofinsulin to its extracellular domain activates a tyrosine-specific protein kinase in the receptor's cytosolic domain. This kinase activates several proteinkinases by phosphorylating specific Tyr residues.The phosphorylated protein kinases bring aboutchanges in metabolism by phosphorylating additional key enzymes, altering their enzymatic activities.A third general class of hormone mechanismsinvolves the coupling of hormone receptors, viaanother group of GTP-binding proteins, to a phospholipase C of the plasma membrane. Hormonebinding activates this enzyme, which hydrolyzesinositol-containing phospholipids in the plasmamembrane. This generates two second messengers:diacylglycerol, which activates protein kinase C,and inositol-l,4,5-trisphosphate (IP3), whichcauses the release of Ca 2+ sequestered in the endoplasmic reticulum.
Ca 2+ is a common second messenger in hormone-sensitive cells and in neuralsignaling; it alters the enzymatic activities of specific protein kinases. Calmodulin is a small Ca2+binding subunit of a number of Ca2+-dependentenzymes.The fourth general transduction mechanismtriggered by hormones is the opening of hormonesensitive ion channels. The nicotinic acetylcholinereceptor is a ligand-gated ion channel, which,when occupied by acetylcholine, allows transmembrane passage of Na + and K+ ions and consequentdepolarization of the target cell. A wave of depolarization sweeps along nerves through the action ofvoltage-gated Na + and Ca 2+ ion channels, triggering neurotransmitter release.A variety of pathological conditions are associated with defects in signal-transduction mechanisms.
Some bacterial toxins interfere with signaltransductions. Oncogenes in a cell's DNA permituncontrolled cell division, possibly through formation of defective signal-transducing proteins thatare insensitive to modulation by growth factors orhormonal signals. Tumor promoters also interferewith cell regulation and growth.Steroid hormones enter cells and bind to specificreceptor proteins.
The hormone-receptor complexbinds specific regions of nuclear DNA called hormone response elements and regulates the expression of nearby genes. Tamoxifen and RU486 aredrugs that act as steroid hormone antagonists.General Background and HistoryNishizuka, Y., Tanaka, C, & Endo, M.
(eds)(1990) The Biology and Medicine of Signal Transduction, Adv. Second Messenger PhosphoproteinRes., 24.A collection of papers on receptor-transducer systems and the medical effects of defective signaltransducers.Further ReadingMolecular Biology of Signal Transduction. (1988)Cold Spring Harb.
Symp. Quant. Biol. 53.This entire volume is filled with short research andreview papers on a wide variety of signal-transducing systems, from bacteria to humans.784Part III Bioenergetics and MetabolismSutherland, E.W. (1972) Studies on the mechanisms of hormone action. Science 177, 401-408.The author's Nobel lecture, describing the classicexperiments on cAMP.Wilson, J.D. & Foster, D.W. (eds) (1992) WilliamsTextbook of Endocrinology, 8th edn, W.B. SaundersCompany, Philadelphia.Especially relevant are Chapter 1, an introductionto hormonal regulation; Chapter 3, on the mechanism of action of steroid hormones; and Chapter 4,on the mechanisms of hormones that act at the cellsurface.Yalow, R.S. (1978) Radioimmunoassay: a probe forthe fine structure of biologic systems.
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