激活突变酪氨酸磷酸酶shp 2参与髓系增殖性疾病的机制探讨-mechanism of activating mutant tyrosine phosphatase shp _ 2 participating in myeloproliferative diseases.docx

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激活突变酪氨酸磷酸酶shp 2参与髓系增殖性疾病的机制探讨-mechanism of activating mutant tyrosine phosphatase shp _ 2 participating in myeloproliferative diseases.docx

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激活突变酪氨酸磷酸酶shp 2参与髓系增殖性疾病的机制探讨-mechanism of activating mutant tyrosine phosphatase shp _ 2 participating in myeloproliferative diseases

组比WT组的髓系细胞集落形成能力增强、肥大细胞中Erk和Akt的磷酸化水平明显升高；SHP-2D61G/+杂合突变后与Gab-2结合能力增高。提示SHP-2D61G/+突变导致髓系细胞发生增殖、重要信号分子Erk、Art的磷酸化水平提高以及突变后SHP-2与Gab2结合能力提高。结论：激活突变的SHP-2D61G/+参与了小鼠髓系增殖性疾病的发生，其分子机制可能是由于激活突变的SHP-2D61G/+与Gab-2结合能力提高，进而参与对IL3介导的Ras-Erk、P13K-Akt信号途径的调节相关。因此，SHP-2可能是髓系细胞高增殖性信号调控的关键分子，及髓系增殖性疾病的发病机制中重要的调控分子之一。关键词：酪氨酸磷酸酶SHP-2;细胞信号通路;髓系增殖性疾病TheMechanismofActivatingMutantTyrosinePhosphataseSHP-2InvolvedinMouseMyeloproliferativeDisordersAbstractAIM:StudytodemostratewhetheractivatingmutanttyrosinephosphataseSHP-2(PT-PN11)involvedinmousemyeloproliferativedisordersornot,apreliminarystudyofthepossiblemolecularmechanismaboutSHP-2participatesinmyeloproliferativedisorders.METHODS:FirstcomparisedwiththenumberofperipheralbloodleukocytesinWT(wild-type)andSHP-2D61G/+mice,andwiththechangeofweek-oldgrowthinrelation-ships（Thatistocomparewiththenumberof8-week-oldand16-week-oldmiceperi-pheralbloodleukocyte）.Usedthespleenof16-week-oldWTandSHP-2D61G/+micetocomparethespleensize,andcalculatedSI(spleenindex=spleenweight(mg)/mouseweight)todeterminetheextentofrelativeincreaseinthespleenwiththespleenof8-week-oldand16-week-oldmice.FCM（FlowCytometry）wasappliedtomeasureMac-1andGr-1ontheperipheralbloodleukocytesurfaceofWTandSHP-2D61G/+mice，andcountedthepositivecellrateofMac-1andthepositivecellrateofTer119(Erythroid),Mac-1andGr-1(Myeloid),CD3(TLymphocytes),B220(BLymphocytes)intheBonemarrowcells.WeusedBMCFU(BoneMarrowColonyformingUnits)toanalysebonemarrowproliferationofWTandSHP-2D61G/+miceandobservedthecellproliferationdifferencesbycounting.GainedmastcellsbyseparatingandculturingfromMyeloidcells,MTSwasusedtoobservecellproliferationofmastcellsinIL3(Interleukin-3alsoknownasmulti-colony-stimulatingfactor，multi-F)stimulation.DetectedthelevelofexpressionandphosphorylationofErkandArtinthebonemarrow-derivedmastcellsbySDSandWesternblot.DetectedthebindingcapacityofSHP-2withGab-2inIL-3stimulationbyWesternblottandIP.Thenumberofleukocytesintheperipheralbloodwasincreaser（P0.05）,spleenswerebiggerinSHP-2D61G/+thaninWT.SI