胰岛素样生长因子Insulinlike growth factor.docx

胰岛素样生长因子Insulinlike growth factor.docx

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胰岛素样生长因子Insulinlikegrowthfactor

胰岛素样生长因子（Insulin-likegrowthfactor）

Insulin-likegrowthfactor

Basicconcept

ShanghaiYaXi（International）snowAmericaauthorizedbiomedicaltechnologyservicescentermarketingPDepartment

Insulin-likegrowthfactors（IGFs）isaclassofmultifunctionalcellproliferationregulatingfactors.Itplaysanimportantroleincelldifferentiation,proliferationandindividualgrowthanddevelopment.ThispaperreviewsthegeneralsituationofIGFsanditsrelationshipwithgrowthanddevelopment.

HistoryofIGFS

GrowthhormoneandDaughadayon1957Salmon（growthhormone,referredtoasGH）intheprocessofgivingfirstfoundinhypophysectomizedratsafterGHserumcanstimulateSintoculturedcartilage,butdirectlyintotheliquidcultureofGHhasnoeffect,sothatGHitselfcandirectlystimulatethegrowthofcartilage,butthrougha"SF"role,thisfactorbecameknownasgrowthregulator.1963Froeshfoundintheseruminsulinlikeeffectonmuscleandfatcellsareonlyasmallpartoftheinsulinantiseruminhibitedtheremainingsolubleinsulinlikeactivitywasnotinhibitedinacidifiedethanol,andnamedNSILASwhichisinhibitedbyinsulinlikeactivity（nonsuppressibleinsulin-likeactivity）.In1972,PieronandTeminpurifiedacytokinefrombovineserumthatstimulatedcelldivision,calledproliferationstimulatingactivity".Aftertheabovethreeexperimentswerecompleted,itwasfoundthattheabovethreesubstanceshadaninhibitoryinsulin-likeactivityandagrowthstimulatoryeffect.Withthedevelopmentofmolecularbiology,1978peoplepurifiedtwokindsofNSILA（I,II）andfounditsstructureandproinsulinwerenamedassimilar,insulin-likegrowthfactorIandII（IGFI,II）toemphasizetheirhomologywithinsulinstructure.ItwasalsoconfirmedthatthesulfationfactorandtheproliferationstimulatingactivityweremembersofthesamepolypeptidefamilyasIGF.

Composition,physicalandchemicalpropertiesofIGFssystem

TheIGFsfamilyiscomposedoftwolowmolecularpolypeptides（IGF-,I,IGF-II）,twospecificreceptorsandsixbindingproteins.IGF-Iisasinglenucleotideproteinwith70aminoacids,themolecularweightof7649Da,heatresistance,whileIGF-IIisasinglestrandedweakacidproteinwith67aminoacids,withamolecularweightof7471Daandstablefor0.1%SDS.Both70%arehomologous,approximately50%ofthestructureandfunctionofhumanproinsulin.ThebiologicalfunctionofIGFsisachievedbybindingtoreceptorsonspecifictargetcellsurfaces.Atpresent,twokindsofIGFreceptorswithdifferentstructuresarefound:

IGF-IreceptorandIGF-IIreceptor（mannose-6phosphatereceptor）,alsoknownastypeIreceptor,typeIIreceptor.Theformerstructureandinsulinreceptor（InsulinreceptorIr）issimilartothatof2beta2glycoproteinfourdimerconsistingofalphaandbetatwosubunitalpha,alphasubunitisaligandbindingsite,betasubunitwithintrinsictyrosinekinaseactivityandtyrosinaseactivity.IGFandinsulin（Insulin,Ins）onIGFreceptoraffinityoftheorderofIrisIns>>IGF-IIGF-II;onIGF-receptor:

IGF-IIGF-II>>Ins;onIGF-IIreceptor:

IGF->IGF-IandInsII,withnocrossreaction.

Unlikeothergrowthfactors,IGFsisassociatedwithaspecificbindingprotein（Binding,Proteins,BPs）inserum,inextracellularfluidandincellcultures,andintheformofinactivecomplexes.Sofar,6IGFBP1,2,3,4,5and6havebeenfound,andtheircharacteristicstructuresconstituteacorrelation.Thesecretoryproteinfamiliesarelowmolecularpeptides,similarinstructureto50%.TheyarehighaffinitywithtwoIGFwithoutbindingtoinsulin.Inthebloodandtissuefluid,theIGFBP3contentishighest,andmorethan80%oftheIGFinthecycleiscombinedwithIGFBP3toformthe150kDathreemolecularcomplex（anunstableacidsubunit,abindingsubunitandIGFpeptide）.IGFBP2,5,6hasahigheraffinitywithIGF-II,andIGFBP1,3,and4aresimilarinaffinitytoIGF-IandIGF-ii.IGFBPhasthefunctionofprolongingthecirculatinglevelofIGFhalf-lifeandstabilizingIGFserumconcentration.Normally,theaffinityofIGFwithitsbindingproteinisgreaterthanorapproximatelyequaltoitsreceptorbinding.Inaddition,thelowexpressionofthehighaffinityreceptorleadstoabalancebetweenasmallamountoffreeIGFandalargenumberofIGF/IGFBPcomplexes.Atpresent,thereareatleastthreemechanismsinvolvedintheactivationofIGF:

（1）parallelmovement.Inspecificcases,suchasgrowth,development,ordamagetotheorganism,highaffinityreceptorsareabundantlyexpressed,competingforIGFandseparatingitfrombindingproteins;

（2）chemicalmodificationofIGForIGFBP,suchasphosphorylation,toreducetheaffinityofthecomplexesanddissociatethem;

（3）bindingproteinhydrolasespecificwatersamplesIGFBPtoreleasetheIGF.

IGFsandgrowthanddevelopment

IGF-IandIGF-IIhavesimilarstructuresandinvitroactivity,buttheirbiologicaleffectsarenotthesame.ThebiologicalfunctionsofIGFsarenotlimitedtomitogenicstimuli,buttheycanalsoinducedifferentiationorpromotetheexpressionofdifferentiatedfunctions.Theprecisebiologicaleffectsdependonthestateofcelldevelopmentandthepresenceofotherhormonesorgrowthfactors.Especiallyindifferenttissuesanddifferentgrowthstages,thereisaconsiderabledifferenceinthefunctionandlevelofIGF-IandIGF-ii.IGF-I,dependentonGH,canpromoteproliferationofmanycellsinvitroandpromoteproteinandDNAsynthesis.ManytissuesandcellsinthebodycanautocrineandparacrineIGF-I.IGF-II,knownasthemajorgrowthfactorbeforebirth,doesnotrequiregrowthhormoneregulationandisexpressedinavarietyoftissuesandorgans.

Studieshaveshownthatinearlypregnancy,trophoblastcellsinvadetheendometriumisstrictlycontrolledbythemicroenvironment;progesteroneregulatingendometriumanddeciduaandvillusdevelopmentandpromoteembryoimplantationaremediatedbyIGFs,themechanismwastoincreasetheadhesionoftheextracellularmatrix,invasionandmigrationofhumantrophoblastcellstostimulate,promoteearlyembryocultivation.InvitroexperimentofKnissandIGFscouldpromoteearlypregnancydeciduaandvilliontransportofglucoseandaminoacids,inadose-dependentmanner,suggestingthatthefetalcirculationbeforetheembryomainlyfromthesurroundingenvironmentandnutrition,throughtheroleofIGFs.Atthesametime,alargenumberofstudieshaveshownthatduringembryonicdevelopment,thelevelofIGF-IImRNAismuchhigherthanthatofIGF-IandmRNA,andhashigherexpressioninembryonictissues.Withtheincreaseofdifferentiationdegree,theexpressionofitdecreases.TheexpressionofmRNAandIGF-Iisaffectedbymanyfactors,alargeincreaseinliver,heartandkidneyafterbirththanbeforebirth;andsignificantlydecreasedinmuscle,stomachandtestisafterbirththanbeforebirth;onlyIGF-inthebrainandlungofmRNAshowedawavychange.ClinicalstudieshaveshownthattheconcentrationofIGF-Iinmaternalcirculationincreasesduringpregnancy,andthatfetalIGF-Iisapproximately15weekspregnant.ThelevelsofIGF-,IandIGFBP1inumbilicalarteryandumbilicalveinweresimilar.Therewasnosignificantdifferencebetweenthetwogroups,indicatingthatthesecretionofIGF-Iinthemotherandfetuswasindependent,andthatIGF-Imightnotpassthroughtheplacenta.SomescholarsdetectedtheconcentrationofcordbloodIGF-I,andtheresultsshowedthatintrauterinefetalgrowthretardation,IGF-incordbloodwaslowerthanthatingestationalagegroupbyabout40%,whilethatofgestationalageIGF-was8%to10%higherthanthatingestationalagegroup.IGFBP1increasedsignificantlyinpreterminfantsandsmallingestationalageinfants,andnegativelycorrelatedwithbirthweight.ThereareserumlevelsandneonatalIGF-Ireportedthebirthweightandlengthwerepositivelycorrelated,andasthemaingrowthfactorbeforethebirthofIGF-IIandtheneonatalbirthheightandweighthavenoobviouscorrelation,anddecreasedrapidlyafterbirth.ArsioIGF-concentrationwasmeasuredinumbilicalcordbloodof131gestationalagebetween19and40weeksofgestationbyumbilicalvascularpuncture.TheresultsshowedthatIGF-Iwaspositivelycorrelatedwithgestationalage.Inconclusion,themechanismofIGFs'sactiononthefetusisnotveryclear,butitsroleinfetalgrowthanddevelopmenthasbeenwidelyrecognized.Thisisalsoconfirmedbygeneticstudies.Growthinhibitionwasfirstobservedat10.5daysafterthemutationofIGF-IandIGF-IIgenes,andtheweightofnewbornratsatbirthwasonly30%ofthenormalweightofwildspecies.Anotherreport:

IGF-IandIGF-IIdeficientmiceorIGF-IIRandIGF-IRhavedefectsinanimalperformancenotonlydwarfmoreserious,only45%wildmice,thesesmallanimalhaveobviousmusclehypoplasia,thenumberoffibercellsinskeletalmuscleandreduceseriousskinhypoplasia.Birthsoftendieofrespiratoryfailure.Inconclusion,theexpressionofeachoftheIGFandIGFreceptorsisessentialfornormalembryoandfetalgrowth,andindicatesthatthetwoareabsentandveryfewothercomponentsareupanddown.Daughadaypointedoutin1988thatpostnatalhumanplasmaIGF-IandIGF-IIconcentrationisinverselyrelatedtopossiblemechanismsforthecompetitionbetweenIGF-BP3

（1）;

（2）bothinhibitthesecretionofGH,andtheGHofIGF-IIGF-IIpositiveregulation;throughthesecretionofGHplayaroleofindirectinhibitionofIGF-I.ItcanbeassumedthatitispreciselybecauseoftheinteractionbetweenIGF-IandIGF-IIthatthebody'sresponseisbalanced.T