By(a)displacinghistonedeacetylasefromthepRBcomplex;(b)acetylationandliberationofE2F1;and(c)drivingpituitarycellsintoSphase(61).HMGA2alsoinducespituitarytumor

By(a)displacinghistonedeacetylasefromthepRBcomplex;(b)acetylationandliberationofE2F1;and(c)drivingpituitarycellsintoSphase(61).HMGA2alsoinducespituitarytumor cyclinB2(CCNB2)anddirectlyinducesCCNB2promotertranscriptionalactivity.GH-secretingtumorscoexpresshighlevelsof CCNB2,HMGA1,andHMGA2(61,62). PTTG.Pituitarytumor ransformingprotein(PTTG),isolated frompituitarytumorcells,facilitatesthespindlecheckpointby actingasasecurintoinhibitseparaseandenablefaithfulsister chromatidseparation(63,64).Pttgmediatesinvitrotransformationandinvivotumorigenesisinmice,andPTTGoverexpression inducesaneuploidywithdysregulatedG2/Mcheckpointsurveillance,resultinginabnormalmitosisandchromosomalinstability (65).PTTGmodulatesp53,participatinginDNAdamage/repairandapoptosis(668).PTTGisabundantlyexpressedinpituitary adenomas(69)andcorrelateswithtumorinvasivenessandrecurrence;itisinducedearlyinestrogen-inducedpituitarytumorigenesis.PTTGelicitspituitarytumorigenesisinatransgenicmodelof pituitary-directedPttgoverexpression,resultinginfocalpituitary hyperplasiaandfunctionaladenomaformation(70). Pituitary senescence.Pituitarycarcinomasareexceedinglyrare,and onlyisolatedcasesofpituitarymetastasesderivedfromGH-secretingadenomashavebeenreported.GH-secretingadenomasthus representanintriguingmodelforstudyingtriggersofmalignant transformation.Cellularsenescencemediatedbyoncogenicpathwaysisassociatedwiththeactivationofinhibitorsofcell-cycle progression(suchasp53-mediatedp21),whichprotectthecell fromproproliferativesignalsandactasabufferagainstmalignanttransformation(71).Prematuresenescencemayaccount fortheoverwhelmingpredominanceofbenignversusmalignant GH-secretingpituitarytumors,asmorethan70 ofGH-secreting tumorsoverexpressPTTG,leadingtoaneuploidyandinduction ofsenescencemarkersincludingp21andsenescence-associated -galactosidase(72).Incontrast,p21isweaklyexpressedinnormal pituitarytissueandundetectableinpituitarycarcinomas.SenescentfeaturesofGH-secretingpituitaryadenomaslikelyconstrain malignanttransformationoftheseinvariablybenignadenomas. Slowreplicativepituitarycell-cycleprogressionisdistinctfromthe rapidcellcycleofskinordigestivetractregenerativetissues(56),…