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Cells use CKIs primarily to helpgovern the activities of Gr/S- and S-Cdks early in the cell cycle.TheCell-CycleControlSystemDependson CyclicalProteolysis\fhereas activation of specific cyclin-Cdk complexes drives progression throughthe Start and G2lM checkpoints (see Figure 17-16), progression through themetaphase-to-anaphasetransition is triggered not by protein phosphorylationbut by protein destruction, leading to the final stagesof cell division.The key regulator of the metaphase-to-anaphasetransition is the anaphasepromoting complex, or cyclosome (APC/C), a member of the ubiquitin ligasefamily of enzymes.As discussed in Chapter 3, many of these enzyrnes are usedin numerous cell processesto stimulate the proteolytic destruction of specificregulatory proteins.
They transfer multiple copies of the small protein ubiquitinto specific target proteins, resulting in their proteolytic destruction by the proteasomes. Other ubiquitin ligases mark proteins for purposes other thandestruction.The APC/C catalyzesthe ubiquitylation and destruction of two major proteins. The first is securln,which normally protects the protein linkages that holdsister chromatid pairs together in early mitosis. Destruction of securin at themetaphase-to-anaphasetransition activatesa protease that separatesthe sistersand unleashes anaphase.The S- and M-cyclins are the second major targets ofthe APCi c. Destroying these cyclins inactivates most cdks in the cell (seeFigure17-16).
As a result, the many proteins phosphorylated by Cdks from S phase toearly mitosis are dephosphorylated by various phosphatasesthat are present inthe anaphase cell. This dephosphorylation of Cdk targets is required for thecompletion of M phase, including the final steps in mitosis and the process ofcytokinesis.Following its activation in mid-mitosis, the APC/c remains active inG1,thereby providing a stable period of Cdk inactivity.
\Mhen G1/S-Cdksare activated in late Gr, the APC/G is turned off, thereby allowing cyclin accumulationto start the next cell cycle.The cell-cycle control system also uses another ubiquitin ligase called SCF(after the names of its three subunits). It ubiquitylates certain cKI proteins inlate G1 and thereby helps control the activation of S-cdks and DNA replication.The APC/C and SCF are both large, multisubunit complexes with somerelated components, but they are regulated differently. APC/C activity changesduring the cell cycle, primarily as a result of changes in its association with anactivating subunit-either cdc20 during anaphase or cdhl from late mitosisthrough early G1.
These subunits help the APC/G recognize its target proteins(Figure l7-2oL). SCF activity also depends on subunits called F-box proteins,which help the complex recognize its target proteins. unlike Apc/c activity,however, scF activity is constant during the cell cycle. ubiquitylation by scF iscontrolled instead by changes in the phosphorylation state of its target proteins,as F-box subunits recognize only specifically phosphorylated proteins (FigureI7-20H.actrvecyclin-Cdkcomplexinactivep27-cyclin-CdkcomprexCdkactivatingphosphateINACTIVEFigure17-18The regulationof Cdkactivity by inhibitory phosphorylation.Theactivecyclin-Cdkcomplexisturnedoff when the kinaseWeel phosphorylatestwo closelyspacedsitesabovethe activesite.Removalof thesephosphatesby thephosphataseCdc25activatesthecyclin-Cdkcomplex.Forsimplicity,onlyone inhibitoryphosphateis shown.CAKaddsthe activatingphosphate,as showni n F i g u r e1 7 - 1 7 .Figure17-19Theinhibitionof acyclin-Cdkcomplex by a CKl.Thisdrawingis basedon the threedimensionalstructureof the humancyclinA-Cdk2complexboundto theCKIp27,as determinedby x-rayp27 bindsto bothcrystallography.Thethe cyclinand Cdkin the complex,distortingthe activesite of the Cdk.ltalsoinsertsinto the ATP-bindingsite,furtherinhibitingthe enzymeactivity.']ua^e elc^o-lleJ JUrJadsE sJaSSulqclq^\Jo qcpe (seqUrMsIpcr-ureqJorq Jo selJasP elPArlJEo1dlsnoluouolnE ^llp4uessa saleJedoqcrq ^ ({JoM-laue ruroJ ol JeqlaSol pe{ul ,r(leuorlcurg are suralord asaq; 'rualsrtslsnqoJIoJluoJ alcdc-gaceqlJo slueuoduroc roferu eqlJo aruos sezrJer.urunsZ-Llelqe;seq)lrMsle)!ueq)otg,o lro/vuaNe sp suolpunl u,lels/(slolluoJ al){)-lle) eql'rrl\/\ou)lun'suonaJEsJeqlo,tueur;osuorlJuryaqllnq-rury a1cl.c-1leJrrlr,roDlqlyv\ sureloJd apocua saua8 asaql;o eruos 'a1r",b1ac aqlSurrnp elellrJso slelel esoqm sVNUur epoJua saua8 aql Jo %0I lnoqe ,aldruexaro; ']sear( Suppnq u1 'Sursrrdrns aJp serpnls esar{l Jo s}FseJ aql 'a1cdcilac eqlq8norqt sassarSord IIaJ aql se auoua8 aqt u1 saua8 eql Jo IIe go uorssardxa aq]ur sa8ueqc azf1eue ot (B Ja]deql ut pessncsrp) sderreorcrur VNC esn ueJ aAA'slleJlsoru ut sle^el uqcdc yorluoc dlaq 'aldruexa ro; 'uorldrrcsuerlaua8 uilcrb ur sa8ueq3 'uorlep8ar;o Ialal leuorlrppp ue sapnord IoJluo3 Ipuou'suratord-drrcsuerl :alamoq 'sadft1ac tsoru Jo salcrb 1ac xaldruoc aJotu eql u1la8rer 4aql puu sase8q uppblqn pue qp3 3o uopeln8ar eqt eAIoAul teql sursru-EqJeru puorldrrcsuerl-lsod uo f1arusn1cxaspuadaploJluoc alcdc-1a3 rnccolou saop uopdlrcsuerl auaB terlJea pessnosrpa1c[c lac cruortrqura 3o4 aql uIuorteln6auleuotldulsuell uo spuadacoslv lotluo) al)/()-lle)seuAzuauorle;r$rnbrqn(1v{osvtJ.oudtrtttX: lO FNOt-LVCVU9tCmnbrqn+(r)))*CJu t a l o l d r o l r q r q u1r P1utlrnbrqn{;od315 Aq srs{;oalord1o lot1uo: 191seu{zuauorle;Ipnbrqn.t'ltunqnsxoq-; rr1>adse Iq pazruboralaq o11a6le1aql smolleiumoqs,ura1o.rdly) aqt se q)ns1a6le1e ;o uor1e1{roqdsoqdaql.sad,{1luaragrp{ueu ate ataql q)tr.lMJo ,sutaloldxoq-l palle)sltunqns6urpurq-elellsqnsuo spuadep115ase611urlrnbrqnaqr 1o,(r;n;lreaql (g) 'eulosealoide ur paper6appue pazrubotatuaql s! 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Oscillations in theactiuities of uarious cyclin-Cdk complexescontrol uariouscell-cycleeuents.Thus,actiuation of S-phasecyclin-Cdk complexes(S-Cdk)initiates S phase,while actiuation ofM-phase cyclin-Cdk complexes(M-Cdk) triggers mitosis. The mechanisms that control the actiuities of cyclin-Cdk complexesinclude phosphorylation of the Cdk subunit, binding of Cdk inhibitor proteins (CIQs),proteolysisof cyclins,and changesin thetranscription of genes encoding Cdk regulators.
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