Download Investigating the role of cell cycle control by Fbxo7 in the

InvestigatingtheroleofcellcyclecontrolbyFbxo7inthe
developmentofT-cellmalignancies
LeadInvestigator:
Co-Investigator:
HeikeLaman
DepartmentofPathology
http://www.path.cam.ac.uk/directory/heike-laman
SuzanneTurner
DepartmentofPathology
http://www.path.cam.ac.uk/directory/suzanne-turner
ThisPhDpositioninthePaediatricCancerProgrammeprovidesauniqueopportunityforahighly
motivatedindividualtoconductresearchwithinestablishedlabsinvestigatingmechanismsofcell
cyclecontrolincancer.Thestudentwillgainskillsandexpertiseintheareasofcellbiologyand
biochemistry,andinthefieldsofcellcycleregulation,Tcellbiology,andinvivomodels.
ProjectDescription
ThederegulationoftheG1/Sphasetransitionoccursregularlyinmultiplecancersubtypes,including
Tcellmalignancies(1).Thiscanhappenasaresultofdirectmutations,includinginactivationof
tumoursuppressorgenes,liketheINK4familymembersofcyclindependentkinase(Cdk)inhibitors,
CDKN2aandCDKN2b,theretinoblastomageneRB1,and/ortheoverexpressionoftheprotooncogenicsubunitsoftheG1phasekinase,Cdk6andcyclinsD2andD3.Interestingly,cyclinD3and
Cdk6arealsoabsolutelyrequiredfortumoursarisingfromtheaberrantactivationofother
oncogenicsignallingpathways,makingthefidelityandfunctionofthispathwaycriticalforcancers,
evenifso-called‘driver’mutationsdonotoccurinitscorecomponents.Forexample,micelacking
Cdk6areresistanttothymiclymphomacausedbyconstitutivelyactiveAktsignalling,whereasmice
lackingcyclinD3arealsofullyresistanttotheaggressivethymiclymphomaresultingfromactivated
Notchsignalling(2;3).TheG1cellcyclepathwayanditscoremachinerythereforerepresent
importantpotentialtherapeutictargets,andunderstandinghowthedisruptionofthiscircuitryaids
tumourdevelopmentandhowthiscanbepreventedisimportant.
OurlaboratoryhasdiscoveredtheF-boxprotein,Fbxo7,hasnon-SCF-dependentactivity,actingasa
cellcycleregulatorthatdirectlystabilisesp27andCdk6,enhancingitsactivationbyD-typecyclins
(4).Fbxo7hasoncogenicactivityasitsover-expressioninp53nullhaematopoieticstemand
progenitorcells(HSPCs)causesT-celllymphomainvivo(5).Morerecently,wehavefoundthatthe
lossofFbxo7expressionrevealedithasopposingrolesoncellproliferationwithintheTcelllineage
atdifferentdevelopmentalstages.Paradoxically,itpromotesproliferationofthymocyteswithinthe
thymus,butrestrainedproliferationofactivatedTcellsintheperiphery.Thiscontradictoryactivity
ofFbxo7indicatesthattheG1phasecircuitryduringTcelldevelopmentisdifferentiallyregulated
fromthatofmatureTcells.ThissetsupthepossibilitythatFbxo7mayberequiredforT-cell
malignanciesderivingfromimmaturethymocytes,butmayactasatumoursuppressorgenein
malignanciesderivingfromperipheralTcells.ThisPhDprojectsetsouttotestthisideadirectlyusing
culturedcelllinesofanumberofimmature(e.g.Tlymphoblasticlymphoma/leukaemia)andmature
Tcellmalignancies(e.g.AnaplasticLargeCellLymphoma;ALCL)todeterminewhetherFbxo7
regulatesthecellcycledifferentiallyinthesedifferenttumourtypesandwhetheritcanpromoteor
suppressoncogenicitydependingonthestageofTcellmaturation,usinginducibleexpressionand
knock-outsystems.Dependingonourfindings,wewilluseaNucleophosmin-AnaplasticLymphoma
Kinase(NPM-ALK)-drivenmousemodelofTcellmalignancythatcanbeengineeredtoariseinthe
thymusortheperiphery(6)totestthetumour-suppressiveortumour-promotingeffectofFbxo7on
tumoursarisingindifferentnicheenvironments.Thestudentwillgainskillsandexpertiseinthe
areasofcellbiologyandbiochemistry,andinthefieldsofcellcycleregulation,Tcellbiology,andin
vivomodels.
References
(1) HanahanD,WeinbergRA.Hallmarksofcancer:thenextgeneration.Cell2011;144(5):646-674.
(2) HuMG,DeshpandeA,EnosM,MaoD,HindsEA,HuGFetal.Arequirementforcyclin-dependent
kinase6inthymocytedevelopmentandtumorigenesis.CancerRes2009;69(3):810-818.
(3) SicinskaE,AifantisI,LeCamL,SwatW,BorowskiC,YuQetal.RequirementforcyclinD3in
lymphocytedevelopmentandTcellleukemias.CancerCell2003;4(6):451-461.
(4) NelsonDE,RandleSJ,LamanH.Beyondubiquitination:theatypicalfunctionsofFbxo7andother
F-boxproteins.OpenBiol2013;3(10):130131.
(5) LomonosovM,MezianeeK,YeH,NelsonDE,RandleSJ,LamanH.ExpressionofFbxo7in
haematopoieticprogenitorcellscooperateswithp53losstopromotelymphomagenesis.PLoS
One2011;6(6):e21165.
(6) MalcolmTI,VillareseP,FairbairnCJ,LamantL,TrinquandA,HookCEetal.Anaplasticlargecell
lymphomaarisesinthymocytesandrequirestransientTCRexpressionforthymicegress.Nat
Commun2016;7:10087.
Applications
Toapplyforthisstudentshiphttp://www.cambridgecancercentre.org.uk/studentships
ForgeneralenquiriespleasecontactTinaThorn [email protected]
Forfurtherinformationorquestionsrelatingtothisprojectpleasecontact
HeikeLaman [email protected]