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Berkeley MCELLBI 110 - Nuclear Receptors and Signaling

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Nuclear Receptors and SignalingHormone activated Txn factorsRegulation by Dimerization andNuclear localizationControlling Cell size andNumber by functionally couplingTranscription and TranslationConnecting Transcription and Signal Transduction PathwaysConnecting Transcription and Signal Transduction PathwaysSequence-specific DNA-binding Transcription Factors :The Gatekeepers of Regulatory Informationand Key Molecular Targets in DiseaseThe Nuclear Hormone Receptor SuperfamilyThyroid and Steroid HormonesVitamins A and DMetabolites- Oxysterols, Bile acidsXenobioticsIntracellular Receptors Regulating Gene ExpressionDNAActivated by lipophilic ligandsderived from diet and environment:LigandSTEROID HORMONE•Steroids are cholesterol-derived hormones that have profound effectson gene transcription.•Examples of steroid hormones are the glucocorticoids, such ascortisol, estrogens, such as β-estradiol, and androgens, such astestosterone.•Cortisol become available shortly before the 1960 presidentialelection and may have had an important influence on the perceivedoutcome of the Kennedy-Nixon television debate. Kennedy sufferedfrom Addison’s disease (inadequate adrenal function).•Anabolic steroids, which are well known in athletics, help buildmuscle mass. They are related to the male sex hormone testosterone.•Testicular feminization is a genetic condition in which genotypic (XY)males are unable to respond to testosterone (for reasons we will cometo presently) and as a consequence develop the phenotypiccharacteristics of a female.Nuclear Receptor LigandsHOW DO STEROID HORMONES WORK?THE ANSWER IS REMARKABLY SIMPLE!•Steroids are lipophilic and hence are able to diffuse across the plasma membraneof cells.•Once inside the cell, the steroid hormone binds to a “nuclear receptor.”•The nuclear receptor is simply a transcription factor that depends on the bindingof the steroid ligand in order to be able to bind to DNA and activate transcription – in analogy to the dependence of CAP on its ligand cyclic AMP.•When its ligand is present, the nuclear receptor binds to a DNA sequenceelement known as a “steroid response element”. For example in the case of theglucocorticoid receptor, the element is known as the glucocorticoid responseelement or GRE.• In some cases, the nuclear receptor is present in the cytoplasm and unable to enter the nucleus and bind to DNA in the absence of the steroid.•XY individuals who exhibit testicular feminization harbor a mutation of the nuclear receptor for testosterone and hence are unable to respond to their own male sex hormone.Stable DNA Binding of RXRheterodimers Depends on Half-SiteSpacing CodeThe “3-4-5” RuleAGGTCA AGGTCANRXR Receptor3 Vitamin D Receptor4 Thyroid HormoneReceptor5 Retinoic Acid ReceptorPositive and Negative Co-Regulators Mediate NR FunctionSignal transduction1. Signal transduction is a pathway that links gene expression inside the cell tosignals emanating from outside the cell.2. Signal transduction is mediated by a receptor that receives the signal andtransduces it into the activation of a transcription factor.3. Nuclear receptors are an extreme example in which the receptor and thetranscription factor are one and the same. This is possible because the signal ( asteroid) is lipophilic and can penetrate the cell.4. Most signal transduction pathways involve signaling molecules (ligands) thatbind to a receptor displayed on the outside surface of the cell membrane (knownas a “cell surface receptor”).5. The receptor transduces the information of ligand binding into events that takeplace on the inside surface of the cell membrane.6. Frequently, the binding of a ligand to a cell surface receptor triggers the activationof an enzyme that modifies a target protein by phosphorylating it (a kinase) orcleaving it (a protease).Control of Gene Expression in a MoreComplex Signaling CascadeControl of Gene Expression in a MoreControl of Gene Expression in a MoreComplex Signaling CascadeComplex Signaling CascadeMetazoans Can Control Cell Number or CellSize to Determine Organ SizeMetazoans CanMetazoans Can Control Cell Number or CellControl Cell Number or CellSize toSize to DetermineDetermine Organ SizeOrgan SizeThe Insulin Receptor Pathway is WellConservedThe Insulin Receptor Pathway is WellThe Insulin Receptor Pathway is WellConservedConserved+Insulin-InsulinInR (inactive)FOXOSTSFOXOSTSNucleusCytoplasmAktInsulin inactivates dFOXO through Insulin inactivates dFOXO through dAktdAktphosphorylationphosphorylationInR (active)FOXOPPPAktFOXOAAAFOXOAAA+InsulinInR (active)AktdFoxo Provides a Novel Feedback Loop in theInsulin Receptor PathwaydFoxo dFoxo Provides a Novel Feedback Loop in theProvides a Novel Feedback Loop in theInsulin Receptor PathwayInsulin Receptor PathwayLow Insulin or Nutrient level leads to 4E-BPLow Insulin or Nutrient level leads to 4E-BPMediated Translation RepressionMediated Translation RepressionInternal Ribosome Entry Sites allowCap-independent TranslationInternal Ribosome EntryInternal Ribosome Entry Sites allowSites allowCap-independent TranslationCap-independent TranslationModified from Holcik & Sonenberg Nat Rev Mol Cell Biol 2005Conditions of High Nutrients or GrowthFactors Activate the dINR pathwayConditions of High Nutrients orConditions of High Nutrients or GrowthGrowthFactors Activate the Factors Activate the dINR dINR pathwaypathwayLow Nutrients or Growth FactorsActivate Foxo FeedbackLow Nutrients orLow Nutrients or Growth FactorsGrowth FactorsActivate Activate Foxo Foxo FeedbackFeedbackSummary Summary••Insulin signaling is conserved fromInsulin signaling is conserved fromDrosophilaDrosophila to man to man••DrosophilaDrosophila FOXO controls FOXO controls growth bygrowth bycontrolling cell numbercontrolling cell number••d4E-BP and Insulin receptor genes ared4E-BP and Insulin receptor genes aretranscriptional targets of transcriptional targets of dFOXOdFOXO••Insulin receptor protein is synthesizedInsulin receptor protein is synthesizeddespite an environment ofdespite an environment of repressedrepressedtranslationtranslation••The 5The 5’’ UTR of insulin receptor confers UTR of insulin receptor confersresistance to translational repression byresistance to translational repression by 4E-BP and thus functionally couples4E-BP and thus functionally couplestranscription activation to translation.transcription activation to translation.InsulinInsulin Signaling


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Berkeley MCELLBI 110 - Nuclear Receptors and Signaling

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