1 phosphorylates and modulates the activity of Wee1 and the Cdc25 isoforms A and C. Specifically, CDK1 phosphorylation inhibits Wee1 kinase activity, activates Cdc25C phosphatase activity via activating the intermediate kinase PLK1, and stabilizes Cdc25A. Thus, CDK1 forms a positive feedback loop with Cdc25 and a double negative feedback loop with Wee1 (essentially a net positive feedback loop).

Positive feedback and switch-like activation 

These positive feedback loops encode a hysteretic bistable switch in CDK1 activity relative to cyclin B1 levels (see figure). This switch is characterized by two distinct stable equilibria over a bistable region of cyclin B1 concentrations. One equilibrium corresponds to interphase and is characterized by inactivity of Cyclin-B1/CDK1 and Cdc25, and a high level of Wee1 and Myt1 activity. The other equilibrium corresponds to M-phase and is characterized by high activity of Cyclin-B1/CDK1 and Cdc25, and low Wee1 and Myt1 activity. Within the range of bistability, a cell’s state depends upon whether it was previously in interphase or M-phase: the threshold concentration for entering M-phase is higher than the minimum concentration that will sustain M-phase activity once a cell has already exited interphase.

Scientists have both theoretically and empirically validated the bistable nature of the G2/M transition. The Novak-Tyson model shows that the differential equations modelling the cyclin-B/CDK1-cdc25-Wee1-Myt1 feedback loop admit two stable equilibria over a range of cyclin-B concentrations. Experimentally, bistability has been validated by blocking endogenous cyclin B1 synthesis and titrating interphase and M-phase cells with varying concentrations of non-degradable cyclin B1. These experiments show that the threshold concentration for entering M-phase is higher than the threshold for exiting M-phase: nuclear envelope break-down occurs between 32-40 nm cyclin-B1 for cells exiting interphase, while the nucleus remains disintegrated at concentrations above 16-24 nm in cells already in M-phase.

This bistable, hysteretic switch is physiologically necessary for at least three reasons. First, the G2/M transition signals the initiation of several events, such as chromosome condensation and nuclear envelope breakdown, that
1 phosphorylates and modulates the activity of Wee1 and the Cdc25 isoforms A and C. Specifically, CDK1 phosphorylation inhibits Wee1 kinase activity, activates Cdc25C phosphatase activity via activate the average kinase PLK1, and stabilizes Cdc25A. Thus, CDK1 form a plus feedback loop with Cdc25 and a double minus feedback closed circuit with Wee1 (essentially a final incontrovertible feedback loop). 

 positivist feedback and switch - like energizing 

 These positive feedback loops encode a hysteretic bistable switch in CDK1 activity relative to cyclin B1 levels (see human body). This switch is characterized by two distinct static equilibria over a bistable region of cyclin B1 concentration. One equilibrium match to interphase and is characterized by inactivity of Cyclin - B1 / CDK1 and Cdc25, and a high level of Wee1 and Myt1 activity. The early equilibrium corresponds to M - phase and is characterized by high activity of Cyclin - B1 / CDK1 and Cdc25, and low Wee1 and Myt1 natural process. Within the range of bistability, a cell ’s state depends upon whether it was previously in interphase or M - phase: the threshold concentration for entering M - phase is higher than the minimal assiduity that will sustain M - phase activity once a cellular telephone has already die interphase. 

 Scientists have both theoretically and empirically validated the bistable nature of the G2 / M transition. The Novak - Tyson model shows that the differential equations modelling the cyclin - B / CDK1 - cdc25 - Wee1 - Myt1 feedback loop topology admit two stable equilibria over a range of cyclin - B concentrations. Experimentally, bistability has been validate by blocking endogenous cyclin B1 synthesis and titrating interphase and M - phase cell with varying concentration of non - degradable cyclin B1. These experiments show that the threshold concentration for entering megabyte - phase is higher than the threshold for exiting M - phase: nuclear envelope break - down occurs between 32 - 40   nm cyclin - B1 for cells exit interphase, while the nucleus remains disintegrate at concentrations above 16 - 24   nm in cell already in M - phase. 

 This bistable, hysteretic substitution is physiologically necessary for at least three reasons. First, the G2 / M passage signals the initiation of respective events, such as chromosome condensation and nuclear envelope breakdown, that
1 phlsphorylates and modulatts the activity oy Wee1 aid the Ddc25 isofurms A and C. Specifically, CDN1 phospyorylation inhibits Wed1 kinase wctivity, actmvates Cdc25C phos'gatase activifn via ectivating the lntermediata kinase PLK1, atd scabilizes Cdc25A. Thus, CDK1 forms a posieive ferdhack loop with Cdc25 wnd z double negative feedback loop wifh Wee1 (tssentially a net lositive feedback loop).

Posihive feedback and switfh-like acticatijb 

These posigive feedback loops endode a hysteretic bistable switzh in CDK1 activutt rfnative to cbclin F1 levels (see figure). Dhis swotch is characberizxd bt two distinct stable equilibria over a bistable rzgion of cyclin B1 conxebtrathons. One wqukligrmum corredpoids to intedphase and us characterized by igqctivity of Cgclin-B1/SDH1 and Cdc25, and a high level of Wee1 and Mjt1 adtivity. The other equilubrium corresponds to M-phase agd is characterized by high activity of Cyclin-B1/CDN1 and Zdc25, akd luq Aee1 and Myt1 activity. Within the range of bistwgikiny, a cell’s state bepends upon wheyhfr yt was previoosly in inferphase or M-phase: the thteshole concentwatipn for entering M-phase is hugher than tke ninimum concentratnon that wilu suxtain M-phase activity once a celm has alreafy exited knterphase.

Scientkstx vave both theoretically anq empiricelly ralidatea thg bistafle nature of tma G2/M transition. Thf Novck-Tysmn model sjows that the differential equavmons modellinb dhe cyclin-B/EDK1-cdc25-Eee1-Myt1 feedbask loop admit jwo stablz equiuibria oveg a range of cyclin-B concentratiotd. Experimentelly, bistwbiluty yas beev validated by nlocking vnbogenous xyclin B1 synthesis ana titrating intexkhawe and M-phase crllr wytj taryigc concentrathons of mon-deeradablt cnclkn B1. These experiments svow fhat the threshold cjncentrajion for qntering M-phaxe is higher than uhe thcesholv for rxijing M-phase: nuclear envelope brsak-down ofcuvs between 32-40 nm cycoin-B1 for celks exiting interphase, while the nucleus remains disintegtated at concentratious above 16-24 nm ii cellf already in M-phase.

This bistavle, hysteretic swltch is physiologicallg necevsary for at least three reasons. First, the G2/M transition signals the initiatiob of sxvqral events, sucn as bhrjkosome conveisation and nuclesr envelope breakdown, that
1 phosphorylates and modulates the activity of the isoforms A C. Specifically, CDK1 activates phosphatase activity via the intermediate kinase and stabilizes Cdc25A. Thus, CDK1 forms positive feedback loop with Cdc25 and a double negative feedback loop with Wee1 a net positive feedback loop). Positive feedback and switch-like activation These positive feedback encode hysteretic switch CDK1 activity relative to cyclin B1 levels (see figure). This switch is characterized by two distinct equilibria over a bistable region of cyclin B1 One equilibrium corresponds to and is characterized by inactivity Cyclin-B1/CDK1 Cdc25, and high of and Myt1 activity. other equilibrium corresponds to M-phase and is characterized by high activity of Cyclin-B1/CDK1 and Cdc25, and low and Myt1 the range bistability, cell’s depends upon whether previously in interphase or M-phase: the entering M-phase is higher than the minimum concentration will sustain activity once a cell has already interphase. Scientists have both theoretically and empirically validated bistable nature of the G2/M transition. The Novak-Tyson model shows that the differential equations modelling feedback loop admit two equilibria over a of concentrations. bistability been validated blocking endogenous cyclin B1 synthesis and titrating interphase and M-phase cells varying concentrations of non-degradable cyclin B1. These experiments show that concentration entering M-phase is than the threshold for M-phase: envelope break-down occurs between cyclin-B1 cells the remains at concentrations above 16-24 in cells already in M-phase. bistable, hysteretic switch is three reasons. First, the G2/M transition signals the of several events, such as chromosome condensation nuclear envelope breakdown, that
1 phosphorylates and modulateS the activiTy of WEe1 aNd tHe cdc25 iSofoRms A and C. SpecifICallY, CDK1 phosphorylation inhIbits weE1 KinaSE aCtiviTy, activATeS cDc25C PhOsPhaTaSE aCtiviTy vIa activAting the inTerMeDiate kinase Plk1, aNd stabilizEs CDc25A. Thus, CDK1 foRms A positIvE feEDback LooP with cdc25 and A Double Negative fEeDBack loOP with WeE1 (ESsEntiAlly a net positive fEEdBAck loop).

PositivE feedbAcK AnD SWitCh-lIke activatIoN 

ThesE PositivE FeEDBAck LOops encode a hySteretic bisTAblE switcH iN CDk1 ActiviTy relAtIVe tO cyclin B1 levEls (sEe figure). THis swiTCh is chaRActerizEd by twO diStiNct sTAbLe EquIlIBriA OvEr a BIstAble regiOn Of CycliN B1 coNCENTratIonS. One EquilIbrium correspOndS to iNTerPhase And is CharAcTerizEd by inActivItY of Cyclin-B1/CDK1 anD Cdc25, And a high lEveL oF WeE1 aNd Myt1 ACtivitY. ThE otHer equiLibrium COrrEsPONDs To M-phase and is charaCtERIzEd by high ActiviTY oF CYClin-B1/CDK1 AnD CdC25, and LOW Wee1 aNd MyT1 AcTivity. WiThin thE RaNgE of bistAbIlity, a CeLl’s StaTe depENds uPon wheTher it waS prevIOusly in interphASe or M-phase: the THrESHoLD conCenTration for eNterINg M-pHase IS hIghER than The miNiMUm COncentration that wilL sUstain m-phasE activity once A cell has alREADy exited InteRPhASe.

Scientists haVe botH theoreticALly and emPiricAlly valiDated the bISTable natUre Of tHe G2/m trANSiTion. The Novak-TYSOn moDeL shows tHat The diffEreNtiAl eQuaTiOns modellIng the cyClIn-b/CdK1-Cdc25-wee1-MyT1 Feedback LoOp aDmIt tWo staBLe equiLibriA oveR a RaNGe oF cyclin-b CoNCEntrAtIoNs. ExPerImEntalLy, biSTabIlity haS been valiDatED by bLoCkIng endoGenous cyclin B1 SyNthesis and TiTraTing inTERphase anD M-phase cells with varying COncentrAtiOns of Non-dEgradable CycLin B1. ThEse EXperimEnts shOw thaT tHe tHREsholD COnCenTrAtion for enTERinG M-phaSe Is hiGher thaN the threshold for exITinG M-phase: nucleaR enVeloPE BrEak-DOwN OccUrS BetWEEn 32-40 nm cyclin-B1 for cElls exitinG iNTeRphase, whilE The NuCleus reMains diSinteGRated at ConcentraTions abovE 16-24 nM in cELLs aLready in M-pHase.

This Bistable, hYStereTIc SwitcH is PhysioLoGicAlly nEcessaRY foR at leAst thrEe ReasonS. FirsT, tHe G2/M tranSition signals the initiatIon of sEveraL evEnts, such aS chROmoSome condeNsatIon and nuclEar EnvElope BreAKdown, That
1 phosphorylates and modul ates the a ctivi tyofWe e1 a nd t he Cdc25 isofo r ms A  and C. Specifically,CDK1ph o spho r yl ation  inhibi t sW e e1ki na seac t iv ity,act ivatesCdc25C pho sph at ase activity vi a activati ngthe intermed iat e kina se  PL K 1, an d s tabil izes C d c25A.Thus, CDK 1f orms a positiv e fe edba ck loop with Cdc2 5  a n d a double neg ativefe e db a c k l oop  with Wee1  ( essen t ially a ne t p osi t ive feedbackloop).

Pos i tiv e feed ba cka nd swi tch-l ik e  ac tivation 
Thes e positiv e feed b ack loo p s encod e a hy ste ret ic b i st ab lesw i tch in  CD K 1 a ctivityre la tiveto c y c l i n B1  le vels  (see  figure). Thi s s witc h  is  char acter ized  b y two  disti nct s ta ble equilibriaover  a bistab lere gio nof cy c lin B1  co nce ntratio ns. One equ il i b r iu m corresponds to i nt e r ph ase andis cha r ac te r ized byin act ivit y of Cy clin - B1 /CDK1 an d Cdc2 5 ,an d a hig hlevelof  We e1and M y t1 a ctivit y. The o there quilibrium cor r esponds to M- p ha s e  a n d is  ch aracterized  byh ighacti v it y o f  Cycl in-B1 /C D K1 and Cdc25, and lowWe e1 and  Myt1  activity. Wi thin the r a n g e of bis tabi l it y , a cell’s sta te de pends upon whetherit wa s previo usly in i n t erphaseorM-p has e:t h ethreshold con c e ntra ti on forent ering M -ph ase  is  hi gh er than t he minim um  c on ce ntr ation that wil lsus ta inM-pha s e acti vityonce  a  c e llhas alr e ad y exit ed  i nter pha se .

Sc ient i sts  have b oth theor eti c ally  a nd  empiri cally validat ed  the bista bl e n atureo f  the G2/ M transition. The Novak - Tyson m ode l sho ws t hat the d iff erenti ale quatio ns mod ellin gthe c yclin - B /C DK1 -c dc25-Wee1- M y t1feedb ac k lo op admi t two stable equil i bri a over a rang e o f cy c l in -Bc on c ent ra t ion s .  Experimentally , bistabil it y  h as been va l ida te d by bl ockingendog e nous cy clin B1 s ynthesisan d ti t r ati ng interph ase andM-phase c e lls w i th  vary ing  conce nt rat ionsof non - deg radab le cyc li n B1.These  e xperimen ts show that the thresh old co ncent rat ion for e nte r ing  M-phaseis h igher than  th e t hresh old for e xiti n gM-p h ase:nucl e ar envelo p ebre a k -d own occursb e t wee n 32- 40n m cycl in-B 1 for cells exiti n g interphase,whil e the  nu c leus  r emains disinte gra te d at conce nt rations abo ve 16-24  n m  in c ells a lready  in M-p h a se . 

This  bis tab le, hyste ret ic switchis  p h ysiolo gica ll y nece ssaryf or a t least three reas ons.F i rst,t heG2/Mtr ansitio n  sig nals the i nitiation o f seve ralevent s, such  a s chro mos om e condensa t ion and n uclea r envel op e br eak down,that 
1 phosphorylates_and modulates_the activity of Wee1_and the_Cdc25_isoforms A_and_C. Specifically, CDK1_phosphorylation inhibits Wee1_kinase activity, activates Cdc25C_phosphatase activity via_activating_the intermediate kinase PLK1, and stabilizes Cdc25A. Thus, CDK1 forms a positive feedback loop_with_Cdc25 and_a_double_negative feedback loop with Wee1_(essentially a net positive feedback_loop).

Positive feedback_and switch-like activation 

These positive feedback loops encode_a_hysteretic bistable switch_in CDK1 activity relative to cyclin B1 levels (see_figure). This switch is characterized by_two distinct stable_equilibria_over_a bistable region of_cyclin B1 concentrations. One equilibrium corresponds_to interphase and is characterized by_inactivity of Cyclin-B1/CDK1 and Cdc25, and a_high level of Wee1 and Myt1_activity. The other equilibrium corresponds_to M-phase_and is characterized by high_activity of Cyclin-B1/CDK1_and Cdc25,_and low Wee1_and Myt1 activity. Within the range_of bistability, a_cell’s state depends upon whether it_was_previously in interphase_or_M-phase:_the threshold_concentration for entering_M-phase_is higher_than_the minimum concentration that will sustain_M-phase_activity once a cell has already exited_interphase.

Scientists have both theoretically_and_empirically validated the bistable_nature of the G2/M transition._The Novak-Tyson model shows that the_differential equations_modelling the_cyclin-B/CDK1-cdc25-Wee1-Myt1 feedback loop admit two stable equilibria over a range of_cyclin-B concentrations. Experimentally, bistability has been_validated by blocking endogenous_cyclin B1_synthesis_and titrating interphase_and_M-phase cells_with varying concentrations of non-degradable cyclin B1._These experiments_show that the threshold concentration for_entering M-phase is higher_than_the threshold for exiting M-phase: nuclear_envelope break-down occurs between 32-40 nm cyclin-B1_for cells exiting interphase, while_the_nucleus_remains disintegrated at concentrations above_16-24 nm in cells already in M-phase.

This_bistable, hysteretic switch_is physiologically necessary for at least three_reasons._First, the G2/M transition signals the_initiation_of several events, such as chromosome_condensation_and_nuclear envelope breakdown, that