8 Регуляция экспрессии генов. Система передачи сигнала (1160077), страница 3
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This inhibitor, when phosphorylated by proteinkinase A, inhibits phosphoprotein phosphatase-1. A rise in the concentration of cAMP therefore stimulates phosphorylation of certain regulated proteins such as glycogen phosphorylase and also slows dephosphorylation of these proteins, prolonging the effect of phosphorylation.Cells contain a family of phosphoprotein phosphatases that hydrolyze specific phosphoserine, phosphothreonine, and phosphotyrosineChapter 22 Integration and Hormonal Regulation of Mammalian Metabolism779esters, releasing Pi. Although this class of enzymes is not yet as thoroughly studied as the protein kinases, it is very likely that these phosphatases will turn out to be just as important as the protein kinases inregulating cellular processes and metabolism.
The known phosphoprotein phosphatases show substrate specificity, acting on only a subset ofphosphoproteins, and they are in some cases regulated by a secondmessenger or an extracellular signal. Some protein phosphatases aretransmembrane proteins of the plasma membrane, with extracellularreceptorlike domains and intracellular phosphatase domains; theymay well prove to be regulated by extracellular signals in a fashionsimilar to regulation of the tyrosine kinase of the insulin receptor.
Thecomplexity and the subtlety of the regulatory mechanisms achieved byevolution strain the imagination, and the experimental challenges ofdiscovering the full range of regulatory mechanisms remain to be met.Steroid and Thyroid Hormones Act in theNucleus to Change Gene ExpressionThe mechanism by which steroid and thyroid hormones exert theireffects is fundamentally different from that for the other types of hormones. Steroid hormones (estrogen, progesterone, and cortisol, for example), too hydrophobic to dissolve readily in the blood, are carried onspecific carrier proteins from the point of their release to their targettissues.
In the target tissue, these hormones pass through the plasmamembrane by simple diffusion and bind to specific receptor proteins inthe nucleus (Fig. 22-39). The hormone-receptor complexes act bySerum binding proteinwith bound hormoneI...HREv— ' StructuralgeneTranslationon ribosomesFigure 22-39 The general mechanism by whichsteroid and thyroid hormones, retinoids, and vitamin D act to regulate gene expression. (I) Hormone (H) carried to the target tissue on serumbinding proteins diffuses across the plasma membrane and binds to its specific receptor protein(Rec) in the nucleus. (2) Hormone binding changesthe conformation of the receptor, allowing it to formdimers in the nucleus with other hormone—receptorcomplexes of the same type and to bind to specificregulatory regions, hormone response elements(HREs), in the DNA adjacent to specific genes.(3) This binding somehow facilitates transcriptionof the adjacent gene(s) by RNA polymerase (Chapter 25), increasing the rate of messenger RNA formation and (4) bringing about new synthesis of thehormone-regulated gene product.
The changed levelof the newly synthesized protein produces the cellular response to the hormone. The details of proteinsynthesis are discussed in Chapter 26.780Part III Bioenergetics and Metabolismbinding to highly specific DNA sequences called hormone responseelements (HREs) (Fig. 22-39) and altering gene expression. Hormonebinding triggers changes in the conformation of the receptor proteinsso that they become capable of interacting with specific transcriptionfactors (Chapter 27). The bound hormone-receptor complex can eitherenhance or suppress the expression (transcription into messengerRNA; Chapter 25) of specific genes adjacent to HREs, and thus thesynthesis of the genes' protein products (Chapter 26).The DNA sequences (HREs) to which hormone-receptor complexesbind are similar in length and arrangement, but different in sequence,for the various steroid hormones.
The HRE sequences recognized by agiven receptor are very similar but not identical; for each receptorthere is a "consensus sequence" (Table 22-10), which the hormonereceptor complex binds at least as well as it binds the natural HREs.Each HRE consensus sequence consists of two six-nucleotide sequences, either contiguous or separated by three nucleotides. The twohexameric sequences occur either in tandem or in a palindromic arrangement (Fig.
12-20). The hormone-receptor complex binds to theDNA as a dimer, with each monomer recognizing one of the six-nucleotide sequences. The ability of a given hormone to alter the expressionof a specific gene depends upon the HRE element's exact sequence andon its position relative to the gene and the number of HREs associatedwith the gene.Table 22-10 Consensus sequences of some hormone responseelementsHormoneSequence of DNA (both strands)*Glucocorticoid(5') AGAACAXXXTGTTCT(3') TCTTGTXXXACAAGA(5') AGGTCAXXXTGACCT(3') TCCAGTXXXACTGGA(5') AGGTCATGACCT (3')(3') TCCAGTACTGGA (5')EstrogenThyroid(3')(5')(3')(5')(strand 1)(strand 2)(strand 1)(strand 2)(strand 1)(strand 2)Source: Data from Schwabe, J.W.R.
& Rhodes, D. (1991) Beyond zinc fingers: steroid hormonereceptors have a novel structural motif for DNA recognition. Trends Biochem. Sci. 16, 291-296;and Fuller, P.J. (1991) The steroid receptor superfamily: mechanisms of diversity. FASEB J. 5,3092-3099.* X represents any nucleotide.Comparison of the amino acid sequences of receptors for severalsteroid hormones as well as receptors for thyroid hormone, vitamin D,and retinoids has revealed several highly conserved sequences andsome regions in which the sequences differ considerably with receptortype (Fig. 22-40). (Retinoids are compounds related to retinoate, thecarboxylate form of vitamin Ax (see Fig. 9-18), which have hormonelikeactions on some cell types.) A centrally located sequence of 66 to 68residues is very similar in all of the receptors; this is the DNA-bindingregion, which resembles regions of other proteins known to bind DNA.All of these DNA-binding regions share the "zinc finger" structure (seeFig.
27-12), a sequence containing eight Cys residues that providebinding sites for two Zn 2+ ions, which stabilize the DNA-binding domain.Chapter 22 Integration and Hormonal Regulation of Mammalian Metabolism/SGH\YAG 20YDN\10 C/ \CV V/\ C/MKETRY//DI50EGA\ C/\\30KiNT\RTNy\y\A///VWS78140KAFFKRSI OGHNDYM/c//Q 60A/c\\\7080RLRKCYEVGMMKGGIRKDRRGGH 3 NHh- COO"TranscriptionDNA bindingactivation(66-68 residues,(variable sequencehighlyand length)conserved)Hormone binding(variable sequenceand length)The region of the hormone receptor responsible for hormone binding (the ligand-binding region, always at the carboxyl terminus) isquite different in different members of the hormone receptor family.The glucocorticoid receptor is only 30% homologous with the estrogenreceptor and 17% homologous with the thyroid hormone receptor.
Inthe vitamin D receptor, the ligand-binding region consists of only 25residues, whereas it has 603 residues in the mineralocorticoid receptor. The different sequences are reflected in different specificities forhormone binding. Mutations that change one amino acid residue inthis region result in loss of responsiveness to a specific hormone; somehumans unable to respond to cortisol, testosterone, vitamin D, or thyroxine have been shown to have such mutations in the correspondinghormone receptor.The specificity of the ligand-binding site is exploited in the use of adrug, tamoxifen, in the treatment of breast cancer in humans.
Insome types of breast cancer, division of the cancerous cells depends onthe continued presence of the hormone estrogen. Tamoxifen competeswith estrogen in binding to the estrogen receptor, but the tamoxifenreceptor complex is inactive in gene regulation. Consequently,tamoxifen administration after surgery or chemotherapy for this typeof breast cancer slows or stops the growth of remaining cancerous cells,prolonging the life of the patient.Another steroid analog, the drug RU486, is used in the very earlytermination of pregnancy. An antagonist of the hormone progesterone,RU486 binds to the progesterone receptor and blocks hormone actionsessential to the implantation of the fertilized ovum in the uterus. As of1992, RU486 had not been approved for use in the United States.The ability of a given steroid or thyroid hormone to act on a specificcell type depends not only on whether the receptor for that hormone issynthesized by the cell, but also on whether the cell contains enzymesthat metabolize the hormone.
Some hormones (testosterone, thyroxine,vitamin D) are enzymatically converted into more active derivativeswithin the target cell; others, such as cortisol, are converted to an inactive form in some cells, making these cells resistant to that hormone.Figure 22-40 The DNA-binding domain commonto a number of steroid hormone receptor proteins.These proteins have a binding site for the hormone,a DNA-binding domain, and a region that activatesthe transcription of the regulated gene.
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