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), consistentwithobservationsthatpituitarytumorsrarelyexhibit malignantphenotypes.Hence,accumulatedpituitaryDNAdamageandsenescence,hallmarksofGH-secretingadenomas,likely enableabenignphenotype.Fuzapladib (sodium) Epigenetic mechanisms LossofgeneexpressionduetoDNAhypermethylationofboth alleles in GH-secreting adenomas exemplifies an epigenetic mechanismbywhichthelossofgenesthatinhibitcellproliferationresultsinpituitarycellproliferation(S21).Lysostaphin CDKN2A encodesCDKinhibitor2A(alsoknownasp16),whichblocksTheJournalofClinicalInvestigation http://www.PMID:23563799 jci.org Volume119 Number11 Novemberscience in medicineFigureDepiction of intracellular pathways associated with somatotroph transformation and proliferation. GH transcription and somatotroph proliferation are induced by cAMP acting through CREB (26). SRIF inhibits cAMP and CREB activity (S43) to suppress GH secretion. Pituitary CDKs most likely exhibit overlapping functions in G1 cell-cycle progression. Somatotroph mitogenic variables consist of POU1F1, GHRH, and GNAS also as endocrine hormones. Mitogenic constraints contain SRIF and tumor suppressor genes, including MEN1. Cell-cycle progression through G/S is mediated by CDKs that phosphorylate Rb to release E2F proteins that drive DNA synthesis. In somatotroph tumors, the cAMP pathway may be constitutively activated. In addition, HMGA2 and PTTG, overexpr.