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Substitution of alanine for either D723 in the B. f 6000chain or R995in the s chain leadsto a high level of spontafo ! qE aoooneous activation, under conditions where the wild-typeg.Echains are inactive.Your advisor suggeststhat you convertE F zooothe aspartatein the B chain to an arginine (D723R)and thearginine in the u chain to an aspartate(R995D).You com0 8 16243240480 8 1624324048pare all three a chains (R995,R995A,and R995D)againstallhourshoursthree B chains (D723,D723A,and D723R).You find that allpairs have a high level of spontaneousactivation, exceptFigureQ19-2Effectsof C/ostridiumtoxinon the barrierfunctionof(the wild Ope) and D723Rvs R995D,which19-7).(A)AdditionMDCKcells(Problemof toxinfromthebasolateral D723 vs R995havelow levels.Basedon theseresults,how do you think the(B)Additionsideof theepithelialsheet.of toxinfromtheapicalsideallbB3 integrin is held in its inactive state?of theepithelialsheet.Thehighertheresistance(ohmscm2),giventhelesstheparacellularforavoltage.currentcytoplasmextracellularrn:fr#"^"723A.
How can it be that two tight junction strands remain,I.-WKLLTT]HDRKEFeven though all of the claudin-4 has disappeared?B. How do you supposethe toxin fragmentcausesthe tightjunction strandsto disintegrate?_. WKVGFFKRNRPC. \Atrydo you supposethe toxin works when it is addedtogJsthe basolateralside of the epithelial sheet, but not when(Problemof ollbB3integrinrepresentationadded to the apical side?FigureQ19-3Schematic(FromP.E.Hughesareindicated,I 9 - I O).TheD723andR995residues19*8 It is not an easymatter to assignparticular functionspermissionfromtheChem.271:6571-6574,1996.Withet al.J.
Biol.to specificcomponentsof the basallamina, sincethe overallBiology')andMolecularfor BiochemistrySocietyAmericanstructure is a complicated composite material with bothmechanicaland signalingproperties.Nidogen,for example,i9 1'l Carboxymethyl Sephadex is a negatively chargedcross-linkstwo central components of the basal lamina bycrosslinked dextran that is commonly used for purifyingbinding to the laminin-yl chain and to type IV collagen.proteins.
It comes in the form of dry beads that swellGiven such a key role, it was surprising that mice with atremendously when added to water. You have packed ahomozygous knockout of the gene for nidogen-l werechromatography column with the swollen gel. \Mhen youentirely healthy, with no abnormal phenory?e. Similarly,start equilibratingthe column with a buffer that contains50mice homozygousfor a knockout of the gene for nidogen-2mM NaCl at neutral pH, you are alarmed to see a massivealso appeared completely normal.
By contrast, mice thatshrinkagein gelvolume.\lVhydoesthe dry Sephadexswellsowere homozygousfor a defined mutation in the gene fordramatically when it is placed in water? \A/try does thelaminin-yl, which eliminatedjust the binding site for nidoswollen gel shrink so much when a salt solution is added?gen,died at birth with severedefectsin lung and kidney formation. The mutant portion of the laminin-yl chain is19-1: At body temperature,L-aspartatein proteins racemtohavenofunctionnidogen,andthoughtotherthan to bindizes to D-aspartateat an appreciablerate. Most proteins indoes not affect laminin structure or its ability to assemblethe body have a very low level of D-aspartate,if it can beinto basal lamina.
How would you explain these geneticdetectedat all. Elastin,however,has a fairly high level of oobservations,which are summarizedin Table Q19-l? \Mhataspartate.Moreover,the amount of D-aspartateincreasesinwould you predict would be the pheno\pe of a mouse thatdirect proportion to the age of the person from whom thewas homozygousfor knockoutsof both nidogen genes?samplewas taken.\A/trydo you supposethat most proteinshave little if any o-aspartate,while elastin has high, age19*9 Discussthe following statement:"The basal laminadependentlevels?of muscle fibers servesas a molecular bulletin board, in19 ":3 Yourbossis coming to dinner!All you havefor a saladwhich adjoining cells can post messagesthat direct the differentiation and function of the underlying cells."is some wilted, day-old lettuce.You vaguelyrecall that there isa trick to rejuvenatingwilted lettuce, but you cant rememberTableQ19-1Phenotypesof micewith geneticdefectsinwhat it is.
Should you soak the lettuce in salt water, soak it inl9-8).componentsof the basallamina(Problemtap water, or soak it in sugar water, or maybe just shine abright light on it and hope that photoslnthesis will perk it up?(A) BASOLATERAL(B) APTCAL= vnonenidogen-l geneknockout(-/-)nonenidogen-2 geneknockout(-/-)nonelaminin-yl nidogenbinding-sitedeletion(+/-)laminin-11nidogenbinding-sitedeletion(-/*) deadat birth/. srandsforhete'ozygous,ho'nozygotrsstandsfo'19*14 The hydraulic conductivity of a singlewater channelis 4.4 x 19 22ttt3 per secondper MPa (megapascal)of pressure. What does this correspond to in terms of watermolecules per second at atmospheric pressure?lAtmospheric pressureis 0.1 MPa (l bar) and the concentrationofwater is 55.5M.l1204Chapter19:CellJunctions,CellAdhesion,and the ExtracellularMatrixREFERENCESGeneralBeckerleM (ed)(2002)CellAdhesionOxford:OxfordUniversiryPressKreisT & ValeR (ed)(,l999)Guidebookto the ExtracellularMatrix,Anchor,and AdhesionProteins,2nd ed Oxford:OxfordUniversityPressMinerJH (ed)(2005)ExtracelularMatrixin Developmentand Drsease(Advancesin DevelopmentalBiology,Vol 15) ElsevierScienceCadherinsand Cell-CellAdhesionGarrodDR,MerrittAJ& NieZ (2002)DesmosomalcadherinsCurrOpinCellBiol14.537-545GumbinerBIV(2005)Regulationof cadherinmediatedadhesioninmorphogenesisNatureRevlr,4olCellBiol6.622-634K ng N, HittingerCT& CarrollSB(2003)Evolutionof keycellsignalingproteinfamiliesandadhesionpredatesanimalor gins Science301:361-363KowalczykAP& ReynoldsAB(2004)yourtail:regulationProtectingofcadherindegradationby p120cateninCurOpinCellBiol16:522-527NelsonWJ& NusseR (2004)Convergenceof Wnt,betacatenrn,andcadherinpathwaysScience303:1483 1487PokuttaS & WeisW (2007)Structureand mechanismof cadherinsandcateninsin ceil-cellcontactsAnnuRevCellDevBlolin pressRosenSD(2004)Ligandsfor L selectrn:homing,inflammatron,ancbeyondAnnuRevlmmunol221)9-156ScheiffeleP,Fan-1,Choihl, FetterR& SerafinT (2000)Neuroliginexpressedin nonneuronalcellstriggerspresynapticdevelopmentincontactingaxonsCel/101:657669ShapiroL,LoveJ & ColmanDR(2007)Adhesionmoleculesin thenervoussystem:structuralinsightsintofunctionand diversity,4nnuRevNeurosci3A451474ShengM & HoogenraadCC(2007)Thepostsynapticarchitectureofexcitatorysynapses.a morequantitativeview AnnuRevBiochem76.823-847TakeichiM (2007)Thecadherinsuperfamry in neuronalconnectionsand interactonsNatureRevNeurosciB:1120VestweberD QAU) Regulationof endothelialcellcontactsduringleukocyteextravasationCurrOptnCellBioll4:5Bl-593YamagataM,SanesJR& WeinerJA (2003)SynapticadhesionmoleculesCurrOpinCellBiol15.621-632YangJ,ManiSA,DonaherJLet al (2004)Twist,a masterregulatorofmorphogenesis,playsan essentiarolein tumormetastasisCel/117.927-939Tight Junctionsand the Organizationof EpitheliaFuruseM, HataM, FuruseK et al (2002)Claudin-basedtightjunctionsarecrucialfor the mammalianepidermalbarrler:a essonfromclaudin-1deficientmiceJ CellBiol156.109911i1lkenouchiJ,FuruseM, FuruseK et ai (2005)Tricellulinconstitutesa novelbarrierat iricellularcontactsof epithelialcellsI CellBiol171.939-945HenriqueD & SchweisguthF (2003)Cellpolarity:the upsanddownsofthe Par6laPKCcomplexCurrOpinGenetDev13:341350NesonWJ(2003)Adaptationof coremechanismsto generatecellpolarilyNcture422:766 774O'BrienLE,.iouTS,PolackAL et al (200,l)Raclorientatesepithellalapicalpolaritythrougheffectson basolaterallamininassemblyNatureCellBtol3:831-B3BSeifertJR& MlodzikM (2007)Frizzed/PCPsignalling:a conservedmechanismregulatingcellpolarityanddirectedmoiilityA/drureReyGenet8:126138ShinK,FoggVC& MargolisB (2006)TighrjunctionsandcellpolarityAnnuRevCellDevBiol22.207-236Passagewaysfrom Cellto Cell:Gap JunctionsandPlasmodesmataCiliaML & JacksonD (2004)PlasmodesmataformandfunctlonCurrOpinCellBtol16:500-506GaienaG,DeerinckTJ,AdamsSRet al (2002)Multicolorandelectronmicroscopicimagingof connexintraffickingScience296:5035OlGoodenoughDA& PaulDL (2003)Beyondthe gap:functionsofunpaired connexonchannels NatureRevA,4oI CelI Biol 4.285-294SegretainD & FalkMM (2004)Regulationof connexinbiosynthesis,gapjunctionformation,and removalBiochimBiophysassembly,Acta1 6 6 2 .
32 1WeiCJ,Xu X & Lo CW(2004)Connexinsinandcellsignalingdevelonmenranddiseas-oAnnuRevCellDevBiol20:811838The BasalLaminaMinerlH & YurchencoPD(2004)Lamininfunctionsin tissuemorphogenesisAnnuRevCellDev8io120.255-284SanesJR (2003)Thebasementmembrane/basallaminaof skeletalmuscleI BlolChem 278.12601-1 2604SasakiR& HohenesterE (2004)Laminin:the cruxofbasementI FasslermembraneassemblyI CellBiol164:959963YurchencoPD,AmentaPS& PattonBt (2004)Basementmembraneassembly,stabilityandactivitiesobservedthrougha developmentalens llatrix Biol22:521-538Integrinsand Cell-MatrixAdhesionGalbraithCG,YamadaKM& SheetzMP(2002)Therelationshipbetweenfarro enAfnr;l rnmnlo' .levelopmentI CellBiol159:695-705HynesRO(2002)Integrins:bidirectional,allostericsignalingmachinesCell110:673687LuoBH& SpringerTA (2006)Integrinstructuresand conformationalsignalingCurrapin CellBtol18.579-586NayalA,WebbDJ& HorwitzAF(2004)Talin:an emergingfocalpointofadhesiondynamicsCurrOpinCellBiol16:9498VogelV & SheetzM (2006)Localforceand geometrysensingregulatecellfunctionsNatureRevMol CellBiol7:265-275The ExtracellularMatrix of Animal ConnectiveTissuesAszodrA, LegateKR,Nakchbandi| & FasslerR (2006)Whatmousemutantsteachus aboutextracellularmatrixfunction,AnnuRevCellD e vB i o2l 2 5 9 16 2 1BulowHE& HobertO (2006)Themoleculardiversityofg ycosaminoglycansshapesanimaldeveiopmentAnnuRevCellDev8io122.375407proteoglycanCouchmanlR (2003)Syndecans:regulatorsof cell-surfacemicrodomains?NatureRevMol CellBiol4.926-937HotaryKB,AllenED,BrooksPCet al (2003)Membranetype I matrixmetalloproteinaseusurpstumorgrowthcontrolimposedby thethree-dimensionalextracellularmatrixCel/114,3345KieltyCM,SherrattMJ& ShuttleworthCA(2002)ElasticfibresJ CellSct115.2817-2828LarsenM, ArtymW, GreenJA& YamadaKM(2006)Thematrixr e o r g a n i z eedx:t r a c e l l uml aar t r i xr e m o d e l i nagn di n t e g r i sn i g n a l i n gCurrOpinCellBrol18:463-471LinX (2004)Functionsof heparansulfateproteoglycansin cellsignalingduringdevelopmentDevelopment131.6009 6021Mon lD & WerbZ (2004)Regulationof marrixbiologyby matrixmetalloproteasesCurrOptnCellBtol16558-564ProckopDJ& KivirikkoKl(1995)Collagens:molecularbiology,diseases,and potentialsfor therapyAnnuRevBiochem64.403-434TooleBP(2001)Hyaluronanin morphogenesissemlnCellDevBiol12:7987The Plant CellWallCarpitaNC& McCannM (2000)TheCellWall In BiochemistryandMolecularBiologyof Plants(BuchananBB,GruissemW & JonesRLeds),pp 52-108Rockville,MD:ASPBCarpitaNC,CampbellM & TlerneyM (eds)(2001)PlantcellwallsPlantMolBiol47.1-340(specialissue)DhuggaKS(2001)Buildingthe wall:genesandenzymecomplexesforpolysaccharidesynthasesCurrOpinPlantBiol4.488-493McCannMC& RobertsK ('1991)Architectureof the primarycellwall1nTheCytoskeletalBasisof PlantGrowthand Form(tloydCWed),pp 109-129London:AcademicPressSmithLG& OppenheimerDG(2005)Spatialcontrolof cellexpansionby the plantcytoskeletonAnnuRevCellDevBiol21:271)95SomervilleC (2006)Cellulosesynthesisin higherplants,AnnuRevCellDevBiol22:53-78sozl'euolJleql uorlElnru VluElnru Suuvror8p Jo JapunoJ e aruoJeq ol puE sroqqSlauslr uuqt Lppeer eJoru eAI Jns puu dlsnoro8rn arour epplp pue rvror8ol lr Sulr,rolle'a8eluunpe e^pceles e'r{.lsnoraBuuplso6'sloJ}uoJIIeJ euo alt8 rteu uoqelmu eprcos aql Supdnrsrp rtyprlualod ,(ep,{-rala suorte}nru acualradxa slleJ Jo suorllrq's11ar'ritarcos JBlnlleJlllnlu e roJ alqnoJlu10I ueql eror.u qlyv\ ^poq ueunq e uluearu .{uorureq slq} tasdn }eq} saJueqJntslp JElnJeloN 'ruquu8ro aqt 5o poo8aql JoJpepeeu se-3ur,{p ro 'Sunenuara3grp'Surpnrp 'Sutlr.or8 '8ur1sal-reuueuralqtsuodsar dlercos E ur seneqeq IIaJ qo€e 'llnsar p sV '(gI raldeq3 ur pessnc-srp) IJE o] rvroqueqlJo qcea Suucarlp 5louuoJ IDlJos se alJes leql qeu8rs repl-leJpJlxa Jo les eleJoqple uu lardralur pue 'aAIaJeJ'pues qlec eql totlreqaq JreqleleurpJooc oI 'uorluJoqelloJ ol pailFuruoJ are usruu8ro JelnllecrlFru p Jo sllaJarp'eAr Jns o1 aladuroc qclqm'euelJeq sBqJns slac 8urnr1-ae4a{rpn'snqJsaua8 urro Jreql Jo sardoc ate8edord o1 dlaq slleo Jrleuoseql 'slleo urra8 aqt Jo e{Bs eql roJ aogrrJes-Jlesrraql ,tg 's33a ro urrads o} eslJsarrr8leql a8eaull 1ac urraB aql;o teql se arues eql sr slleo olleruos aqtgo auoua8aql pue '33a pazlppa; 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]noqp 1lun esrJpe{Jpru p Moqs lou pp qese8e51pue eurqsoJrH ur serua{nal Jo aJuaprJur aql ,{geyurrg 'Suqous dleaq;o sreaf'aldurexe JoJ Taf,uec3un1 aJuap0Z JaUe []un .,{ldaalsasrr o} ur8aq lou saopJo-rJur aqJ'tua8e psnec aql ol arnsodxaJaUe3uo1ylun lueJudde eruoJeq /tllensn]ou seop aseasrpaql 'asneJ Ieuralxa crJrJadsE e^Bq 01 Ulltou>IsJeJuEcasoql roCslla) luerraqv/(l6ursearlulurorJIllenpelg dola^acsta)ue)'Journ] e;oluarudola^ap aq] pue qlvror8IIaJ snoJaruec alouord ol aleradooJ ueJ IIaJ a18urse ur sluala crlaua8 aldrl1nru]Eq] SurlBJlsuouap 'suorlelnru a13ursqlr,r,raoru ueqt JalspJJaJueJ dolarrapaua8'aJotuJeqlJnCIeJrlrJJ-Jerueceuo ueql aJour ur suorleln(u qll,tr ecru paraaur8ua'do1a,l,apo] reJuef, ro; dressacauale sluana clleua8 raqlo ]Bq] 8ur.{1drurz(poqaqtur sllaoJo lasqns parellecs ilerus e ur.,(1uosasrJepue sqtuoru Jo porrad 3e1E JaUera)ue) :02JaldeqfOLZLCANCERASA MICROEVOLUTIONARYPROCESSN O R M A LE P I T H E L I U M1211NTRAEPITHELIAH I G H - G R A DIENEOPLASIALOW-GRADEINTRAEPITHELIANEOPLASIAINVASIVECARCINOMAooocc(B)(c)(D)#Figure20-9 The stagesof progressionin the development of cancerof the epithelium of the uterine cervix.Pathologiststhey see,so asto guidethe choiceofusestandardizedterminologyto classifythe typesof disorderstreatment.(A)In the normalstratifiedsquamousepithelium,dividingcellsareconfinedto the basallayer.(B)In low-gradecellsareintraepithelialneoplasia,dividingcellscan be foundthroughoutthe lowerthird of the epithelium;the superficial(C)In high-gradeintraepithelialcellsin allneoplasia,stillflattenedand showsignsof differentiation,but this is incomplete.(D)Truemalignancybeginswhen the cellsmovethe epitheliallayersareproliferatingand exhibitdefectivedifferentiation.throughor destroythe basallaminathat underliesthe basallayerof epitheliumand invadethe underlyingconnectivetissue.(Photographscourtesyof AndrewJ.Connolly.)CervicalCancersAre Preventedby EarlyDetectionThe epithelium covering the cervix is initially organized as a stratified (multilayered) squamous epithelium (Figure 20-9A), which is similar in structure to theepidermis of the skin (seeFigure 23-3).In such stratified epithelia, cell proliferation normally occurs only in the basal layer, generating cells that stop dividingand then move out toward the surface, differentiating as they move to form flattened, keratin-rich cells that are eventually sloughed off when they reach thesurface.
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