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It wouldclearly be disastrous, for example, if events like chromosome condensation ornuclear envelope breakdor.trnwere only partially initiated or started but notcompleted. Second, the cell-cycle control system is remarkably robust and reliable, partly because backup mechanisms and other features allow the system tooperate effectively under a variety of conditions and even if some componentsfail.
Finally, the control system is highly adaptable and can be modified to suitspecific cell types or to respond to specific intracellular or extracellular signals.In most eucaryotic cells, the cell-cycle control system triggers cell-cycle progression at three major regulatory transitions, or checkpoints (see FigureI7-I4).The first checkpoint is Start (or the restriction point) in late Gr, where thecell commits to cell-cycle entry and chromosome duplication, as mentionedearlier.
The second is the GzlM checkpoint, where the control system triggersthe early mitotic events that lead to chromosome alignment on the spindle inmetaphase.The third is the metaphase-to-anaphase transition, where the control system stimulates sister-chromatid separation, leading to the completion ofmitosis and cytokinesis.The control system blocks progression through each ofthese checkpoints if it detects problems inside or outside the cell. If the controlsystem sensesproblems in the completion of DNA replication, for example, itwill hold the cell at the G2iM checkpoint until those problems are solved.
Similarly, if extracellular conditions are not appropriate for cell proliferation, thecontrol system blocks progression through Start, thereby preventing cell division until conditions become favorable.Figure'17-14Thecontrol of the cellcycle.A cell-cyclecontrolsystemtriggersprocessesof the cellcyclethe essentialmitosis,andsuchas DNAreplication,controlsystemiscytokinesis.Therepresentedhereas a centralarm-thecontroller-that rotatesclockwise,processeswhen ittriggeringessentialon the outerreachesspecificcheckpointsdial.Informationaboutthe completionofevents,aswell as signalsfromcell-cyclecancausethe controlthe environment,systemto arrestthe cycleat theseThe mostProminentcheckpoints.occurat locationsmarkedcheckDointswith vellow boxes.1062Chapter17:TheCellCycleTheCell-CycleControlSystemDependson CyclicallyActivated(Cdks)Cyclin-DependentProteinKinasesCentral components of the cell-cycle control system are members of a family ofprotein kinases knor,rm as cyclin-dependent kinases (Cdks).
The activities ofthese kinases rise and fall as the cell progressesthrough the cycle, leading tocyclical changes in the phosphorylation of intracellular proteins that initiate orregulate the major events of the cell cycle. An increase in Cdk activity at theG2lM checkpoint, for example, increasesthe phosphorylation of proteins thatcontrol chromosome condensation, nuclear envelope breakdown, spindleassembly,and other events that occur at the onset of mitosis.Cyclical changes in Cdk activity are controlled by a complex array ofenzymes and other proteins that regulate these kinases.The most important ofthese Cdk regulators are proteins known as cyclins. Cdks, as their name implies,are dependent on cyclins for their activity: unless they are tightly bound to acyclin, they have no protein kinase activity (Figure f7-f 5). Cyclins were originally named becausethey undergo a cycle of syrthesis and degradation in eachcell cycle.The levels of the cdk proteins, by contrast, are constant, at least in thesimplest cell cycles.
Cyclical changes in cyclin protein levels result in the cyclicassembly and activation of the cyclin-cdk complexes; this activation in turntriggers cell-cycle events.There are four classesofcyclins, each defined by the stageofthe cell cycle atwhich they bind cdks and function.
All eucaryotic cells require three of theseclasses(Figure l7-f 6):l. G1/S-cyclins activate Cdks in late Gr and thereby help trigger progressionthrough Start, resulting in a commitment to cell-cycle entry. Their levelsfall in S phase.2. S-cyclins bind Cdks soon after progression through Start and help stimulate chromosome duplication. S-cyclin levels remain elevated until mitosis, and these cyclins also contribute to the control of some early mitoticevents.3. M-cyclins activate Cdks that stimulate entry into mitosis at the G2lMcheckpoint.
Mechanisms that we discuss later destroy M-cyclins in midmitosis.In most cells, a fourth class of cyclins, the Gl-cyclins, helps govern the activitiesof the Gr/S cyclins, which control progression through Start in late G1.In yeast cells, a single cdk protein binds all classesof cyclins and triggers different cell-cycle events by changing cyclin partners at different stages of thecycle. In vertebrate cells, by contrast, there are four cdks. TWointeract with Grcyclins, one with G1/S-and S-cyclins,and onewith M-cyclins. In this chapter, wesimply refer to the different cyclin-Cdk complexes as G1-Cdk, Gr/S-Cdk, S-Cdk,and M-Cdk.
Thble l7-l lists the names of the individual Cdks and cyclins.How do different cyclin-cdk complexes trigger different cell-cycle events?The answer, at least in part, seems to be that the cyclin protein does not simplyactivate its cdk partner but also directs it to specific target proteins. As a result,G,iS-cyclin',,GrtMi _ -m e t a p h a s e - a n a p h a s eiMAPC/CGr/s-CdkS-CdkG1cyclin-dependent(Cdk)kinaseFigure17-15Two key componentsofthe cell-cyclecontrol system.Whencyclinformsa complexwith Cdk,theprotein kinaseis activatedto triggerspecificcell-cycleevents.Without cyclin,Cdkis inactive.Figure 17-16 Cyclin-Cdkcomplexesofthe cell-cyclecontrol system.Theconcentrationsof the three major cyclintypesoscillateduringthe cellcycle,whilethe concentrationsof Cdks(not shown)do not changeand exceedthe amountsof cyclins.In lateG1,risingG1lS-cyclinlevelslead to the formationof G1lS-Cdkcomplexesthat triggerprogressionthroughthe Startcheckpoint.S-Cdkcomplexesform at the start of S phaseand triggerDNAreplication,aswell assomeearlymitotic events.M-Cdkcomplexesform duringG2but areheld inan inactivestateby mechanismswedescribelater.Thesecomplexesareactivatedat the end of G2and triggertheearlyeventsof mitosis.A separateregulatoryprotein,the APC/C,which wediscusslater,initiatesthe metaphase-toanaphasetransition.THECELL.CYCLECONTROLSYSTEM1063Table17-1TheMajorCyclinsandCdksof VertebratesandBuddingYeastG1-CdkGrlS-Cdk5-CdkM-CdkcyclinD*cyclinEcyclinAcyclinBCdk4 Cdk6CdkzCdk2,Cdkl**CdklCln3Cln1,2c l b s ,6clb1,2,3,4cdkl "*cdklcdklcdklD1,D2,and D3)" TherearethreeD cyclinsin mammals(cyclins**The originalnameof Cdkl wasCdc2in bothvertebratesandflssionyeast,and Cdc2Binbuddingyeasteach cyclin-Cdk complex phosphorylates a different set of substrate proteins.The same cyclin-Cdk complex can also induce different effects at different timesin the cycle, probably because the accessibility of some Cdk substrateschangesduring the cell cycle.
Certain proteins that function in mitosis, for example, maybecome available for phosphorylation only in G2.Studies of the three-dimensional structures of Cdk and cyclin proteins haverevealed that, in the absence of cyclin, the active site in the Cdk protein is partlyobscured by a slab of protein, like a stone blocking the entrance to a cave (Figurel7-L7A).
Cyclin binding causesthe slab to move away from the active site, resulting in partial activation of the Cdk enz)ryne(Figure l7-l7B). Full activation of thecyclin-Cdk complex then occurs when a separate kinase, the Cdk-activatingkinase (CAK), phosphorylates an amino acid near the entrance of the Cdk activesite. This causes a small conformational change that further increases the activity of the Cdk, allowing the kinase to phosphorylate its target proteins effectivelyand thereby induce specific cell-cycle events (Figure I7-I7C). <TAGA>CanInhibitoryPhosphorylationand CdkInhibitoryProteins(CKls)SuppressCdkActivityThe rise and fall of cyclin levels is the primary determinant of Cdk activity during the cell cycle.
Several additional mechanisms, however, fine-tune Cdk activity at specific stagesofthe cycle.Phosphorylation at a pair of amino acids in the roof of the kinase active siteinhibits the activity of a cyclin-Cdk complex. Phosphorylation of these sites by aprotein kinase knor,vn as Weel inhibits Cdk activity, while dephosphorylation ofthese sites by a phosphatase knor,rm as Cdc25 increases Cdk activity (Figure17-18).
We will see later that this regulatory mechanism is particularly important in the control of M-Cdk activity at the onset of mitosis.Binding of Cdk inhibitor proteins (CKIs) also regulates cyclin-Cdk complexes. The three-dimensional structure of a cyclin-Cdk-CKl complex revealsCdk-activatingkinase(CAK)cyclinactivesite(A)TNACTTVE(B) PARTLYACTIVEactivating phosphate(c)Figure 17-17 The structuralbasisof Cdkactivation.Thesedrawingsare basedonof humanstructuresthree-dimensionalCdk2,as determinedby x-raylocationof the boundcrystallography.Theenzymeis showninATPis indicated.Thethree states.(A) In the inactivestate,withoutcyclinbound,the activesite is blockedby aregionof the proteincalledthe T-loop(red).(B)The bindingof cyclincausesthe T-looptomove out of the activesite,resultinginpartialactivationof the Cdk2.(C)Phosphorylationof Cdk2(by CAK)at athreonineresiduein the T-loopfurtherthe enzymeby changingthe shapeactivatesof the T-loop,improvingthe abilityof theenzymeto bind its protein substrates.1064Chapter17:TheCell Cyclethat CKI binding stimulates a large rearrangement in the structure of the Cdkactive site, rendering it inactive (Figure f 7-fg).
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