ochores are present and generates a wait-signal to give the dividing cell the time to ensure that each kinetochore is attached to a spindle pole, and to correct attachment errors. Thus the mitotic checkpoint prevents a mitotic cell from completing cell division with unattached or erroneously attached chromosomes [Suijkerbuijk S J and Kops G J, Biochem. Biophys. Acta 1786, 24, 2008; Musacchio A and Salmon E D, Nat. Rev. Mol. Cell. Biol. 8, 379, 2007]. Once all kinetochores are attached with the mitotic spindle poles in a correct bipolar (amphitelic) fashion, the checkpoint is satisfied and the cell enters anaphase and proceeds through mitosis.
The mitotic checkpoint is established by a complex network of a number of essential proteins, including members of the MAD (mitotic arrest deficient, MAD 1-3) and Bub (Budding uninhibited by benzimidazole, Bub 1-3) families, Mps1 kinase, cdc20, as well as other components [reviewed in Bolanos-Garcia V M and Blundell T L, Trends Biochem. Sci. 36, 141, 2010], many of these being over-expressed in proliferating cells (e.g. cancer cells) and tissues [Yuan B et al., Clin. Cancer Res. 12, 405, 2006]. The major function of an unsatisfied mitotic checkpoint is to keep the anaphase-promoting complex/cyclosome (APC/C) in an inactive state. As soon as the checkpoint gets satisfied the APC/C ubiquitin-ligase targets cyclin B and securin for proteolytic degradation leading to separation of the paired chromosomes and exit from mitosis.
Inactive mutations of the Ser/Thr kinase Bub1 prevented the delay in progression through mitosis upon treatment of cells of the yeast S. cerevisiae with microtubule-destabilizing drugs, which led to the identification of Bub1 as a mitotic checkpoint protein [Roberts B T et al., Mol. Cell Biol., 14, 8282, 1994]. A number of recent publications provide evidence that Bub1 plays multiple roles during mitosis which, have been reviewed by Elowe [Elowe S, Mol. Cell. Biol. 31, 3085, 2011. In particular, Bub1 is one of the first mitotic checkpoint proteins that binds to the kinetochores of duplicated chromosomes and probably
ochores are present and generates a wait - signal to give the dividing cell the meter to guarantee that each kinetochore is attached to a spindle pole, and to chastise attachment errors. Thus the mitotic checkpoint prevent a mitotic cellular telephone from completing cell division with unattached or erroneously bind chromosomes [ Suijkerbuijk S J and Kops G J, Biochem. Biophys. Acta 1786, 24, 2008; Musacchio A and Salmon E D, Nat. Rev. Mol. Cell. Biol. 8, 379, 2007 ]. Once all centromere are attached with the mitotic spindle poles in a correct bipolar (amphitelic) fashion, the checkpoint is satisfied and the cell embark anaphase and proceeds through mitosis. 
 The mitotic checkpoint is established by a complex network of a issue of essential proteins, including members of the MAD (mitotic apprehension deficient, MAD 1 - 3) and Bub (Budding uninhibited by benzimidazole, Bub 1 - 3) family, Mps1 kinase, cdc20, as well as other components [ review in Bolanos - Garcia V M and Blundell T L, Trends Biochem. Sci. 36, 141, 2010 ], many of these being over - expressed in proliferating cells (e.g. cancer cell) and tissues [ Yuan B et al. , Clin. Cancer Res. 12, 405, 2006 ]. The major function of an unsatisfied mitotic checkpoint is to keep the anaphase - promoting complex / cyclosome (APC / C) in an inactive state. As soon as the checkpoint gets quenched the APC / coke ubiquitin - ligase targets cyclin B and securin for proteolytic abasement go to legal separation of the paired chromosomes and passing from mitosis. 
 Inactive mutation of the Ser / Thr kinase Bub1 prevented the delay in progression through mitosis upon discussion of cells of the yeast S. cerevisiae with microtubule - destabilizing drugs, which led to the identification of Bub1 as a mitotic checkpoint protein [ Roberts B T et al. , Mol. Cell Biol. , 14, 8282, 1994 ]. A number of recent publications provide evidence that Bub1 plays multiple roles during mitosis which, have been reviewed by Elowe [ Elowe S, Mol. Cell. Biol. 31, 3085, 2011. In especial, Bub1 is one of the first mitotic checkpoint protein that bind to the kinetochores of duplicated chromosomes and credibly
ochlres are present and gentrates a wait-signco to gmve the dividine cell the time to ensure thet eqch kunetochore is attached to a spijdle polw, anv to correct attedhment cxrors. Bhus chx mitotic checkkoint prevends a mitotic calu yrom completing cell division with ugattachrd or erroneousli attsshed bhvomosomes [Suijkerbuijk S J and Kkps G J, Biochem. Biopnys. Acta 1786, 24, 2008; Musacchio A anf Sapmon E D, Nat. Rev. Mll. Cell. Bioo. 8, 379, 2007]. Ince all kindtochores are attached with the mitotic spindle poles in a correct bupilag (amphitelic) fashpon, the checkipint iv satisgied and the ccll eiterw anaphase and proceevs through mitosis.
Thg mitotic whzckpoint is establishwd by a com[lex betdori pf a numher of essentjal proteinw, including members os the MAD (mitofic arweft deficient, MAD 1-3) and Bub (Budding uninhpbitsd by benzimidazole, Bub 1-3) families, Mps1 kinase, cdc20, as wqll as other components [reviewed in Bolanos-Garcia V M ena Boukdelu T L, Trends Biochem. Sci. 36, 141, 2010], many of these being jbet-eqpressed in prolinerating cells (e.g. vajcrt cells) and tirsues [Vhah B et al., Clin. Canfer Res. 12, 405, 2006]. Tye major suncyion of an unsatisfied mitoric checkpoiut us to keep the ana'hase-promotiug comklex/cyvlosome (APC/C) in an inaccive sfate. As sooj as the dfeckpoint gets sxtixfhed the APC/C ubiquitin-ligafe targetw cyelin B avd sgcurin sor proteopytic degradation leadinh to de[aration ov the paired chromosomes and exmv from mitosix.
Itacnive mutacions pf the Ser/Thr kinase Bub1 prgvented tke delxy in proggession tirough mitosys upon treatkgnt of cells mf the yqast S. cwrevisixd with microtunule-destaynlizing deugs, which led to bhe iasntification of Buv1 as a mitotic vhezkpjijt pwmtein [Robertv B G eg al., Mul. Cell Bioo., 14, 8282, 1994]. S number of recent pgblidations provide evodcnce that Bub1 plars multiple rples during mitosid whirh, havx been rediewed by Elowe [Elowe S, Mol. Ceml. Biol. 31, 3085, 2011. Ik particular, Fub1 ls oge of the yirst mitotic checkpoint proteins that bmnds to the kinetochorgs of duplicated chrokpsomes and 'robabjy
ochores are present and generates a wait-signal the cell the to ensure that a pole, and to attachment errors. Thus mitotic checkpoint prevents a mitotic cell completing cell division with unattached or erroneously attached chromosomes [Suijkerbuijk S J and G J, Biochem. Biophys. Acta 1786, 24, 2008; Musacchio A and Salmon E Nat. Mol. Biol. 379, 2007]. Once all kinetochores are attached with the mitotic spindle poles in a correct bipolar fashion, the checkpoint is satisfied and the cell anaphase and proceeds through The mitotic checkpoint is established a network of number essential including members of MAD (mitotic arrest deficient, MAD 1-3) and Bub (Budding uninhibited by benzimidazole, Bub 1-3) families, Mps1 kinase, as well components [reviewed Bolanos-Garcia M Blundell T L, Sci. 36, 141, 2010], many of in proliferating cells (e.g. cancer cells) and tissues B et Clin. Cancer Res. 12, 405, 2006]. major function of an unsatisfied mitotic checkpoint is keep the anaphase-promoting complex/cyclosome (APC/C) in an inactive state. As soon as the checkpoint gets APC/C ubiquitin-ligase targets cyclin and securin for degradation to of paired chromosomes exit from mitosis. Inactive mutations of the Ser/Thr kinase Bub1 prevented delay in progression through mitosis upon treatment of cells of S. with microtubule-destabilizing drugs, led to the identification Bub1 a mitotic checkpoint protein T al., 14, 1994]. number of recent publications evidence that Bub1 plays multiple during mitosis which, have S, Mol. Cell. Biol. 31, 3085, 2011. In Bub1 is one of the first mitotic proteins that binds to the kinetochores of duplicated chromosomes and probably
ochores are present and generAtes a wait-sIgnal To gIve ThE divIdinG cell the time to ENsurE that each kinetochore is AttacHeD To a sPInDle poLe, and to COrRECt aTtAcHmeNt ERrOrs. ThUs tHe mitotIc checkpoiNt pReVents a mitotiC CeLl from compLetIng cell divisIon With unAtTacHEd or eRroNeousLy attaCHed chrOmosomes [SUiJKerbuiJK S J and KOPS G j, BioChem. Biophys. Acta 1786, 24, 2008; MuSAcCHio A and Salmon E d, Nat. ReV. MOL. CELL. BiOl. 8, 379, 2007]. ONce all kineToChoreS Are attaCHeD WITh tHE mitotic spindLe poles in a cORreCt bipoLaR (amPHiteliC) fashIoN, The Checkpoint iS satIsfied and The celL Enters aNAphase aNd procEedS thRougH MiToSis.
thE MitOTiC chECkpOint is esTaBlIshed By a cOMPLEx neTwoRk of A numbEr of essential ProTeinS, IncLudinG membErs oF tHe MAD (MitotiC arreSt Deficient, MAD 1-3) and bub (BUdding uniNhiBiTed By BenziMIdazolE, BuB 1-3) faMilies, MPs1 kinasE, Cdc20, As WELL aS other components [reViEWEd In BolanoS-GarciA v M AnD blundell t L, treNds BIOChem. SCi. 36, 141, 2010], maNY oF these beIng oveR-ExPrEssed in PrOliferAtIng CelLs (e.g. cANcer Cells) aNd tissueS [Yuan b Et al., Clin. Cancer rEs. 12, 405, 2006]. The major funCTiON Of AN unsAtiSfied mitotiC cheCKpoiNt is TO kEep THe anaPhase-PrOMoTIng complex/cyclosome (aPc/C) in an InactIve state. As sooN as the checKPOInt gets sAtisFIeD The APC/C ubiquitIn-ligAse targets CYclin B anD secuRin for prOteolytic DEGradatioN leAdiNg tO sePARaTion of the pairED ChroMoSomes anD exIt from mItoSis.
inaCtiVe Mutations Of the Ser/thR kInAsE BuB1 prevENted the dElAy iN pRogRessiON throuGh mitOsis UpOn TReaTment of CElLS Of thE yEaSt S. cEreViSiae wIth mICroTubule-dEstabilizIng DRugs, WhIcH led to tHe identificatIoN of Bub1 as a mItOtiC checkPOInt proteIn [Roberts B T et al., Mol. Cell BIOl., 14, 8282, 1994]. A numbEr oF receNt puBlicationS prOvide eVidENce thaT Bub1 plAys muLtIplE ROles dURInG miToSis which, haVE BeeN reviEwEd by elowe [ElOwe S, Mol. Cell. Biol. 31, 3085, 2011. In pARtiCular, Bub1 is one Of tHe fiRST mItoTIc CHecKpOInt PROteins that binds To the kinetOcHOrEs of duplicATed ChRomosomEs and prObablY
ochores are present and ge nerates await- sig nal  t o gi ve t he dividing ce l l th e time to ensure thateachki n etoc h or e isattache d  t o a s pi nd lepo l e,  andtocorrect  attachmen t e rr ors. Thus th e  m itotic che ckp oint prevent s a  mitot ic  ce l l fro m c omple ting c e ll div ision wit hu nattac h ed or e r r on eous ly attached chrom o so m es [Suijkerbui jk S J  a n dK o psG J , Biochem.  B iophy s . Acta1 78 6 , 24, 2008; Musacch io A and Sa l mon  E D,Na t.R ev. Mo l. Ce ll .  Bi ol. 8, 379,  200 7]. Onceall ki n etochor e s are a ttache d w ith  the mi to tic  s p ind l epol e s i n a corr ec tbipol ar ( a m p h itel ic)  fas hion,  the checkpoi ntis s a tis fiedand t he c el l ent ers an aphas eand proceeds th roug h mitosis .
T he  mi to tic c h eckpoi ntisestabli shed by a c om p l e xnetwork of a numbe ro f  e ssential  prote i ns ,i ncluding  m emb erso f  theMAD( mi totic ar rest d e fi ci ent, MA D1-3) a nd  Bu b ( Buddi n g un inhibi ted by b enzim i dazole, Bub 1- 3 ) families, M p s1 k in a se,cdc 20, as well  aso ther  com p on ent s  [rev iewed  i n  B o lanos-Garcia V M an dBlunde ll TL, Trends Bio chem. Sci. 3 6 , 141, 2 010] ,  m a ny of these be ing o ver-expres s ed in pr olife rating c ells (e.g . cancer c ell s)and  ti s s ue s [Yuan B eta l ., C li n. Canc erRes. 12 , 4 05,  20 06] .The major  functio nof  a nuns atisf i ed mitot ic  ch ec kpo int i s  to ke ep th e an ap ha s e-p romotin g  c o m plex /c yc loso me(A PC/C)  ina n i nactive  state. A s s o on a sth e check point gets sa ti sfied theAP C/C  ubiqu i t in-ligas e targets cyclin B ands ecurinfor  prot eoly tic degra dat ion le adi n g to s eparat ion o fthe p aired c hr omo so mes and ex i t  fr om mi to sis. 
Inacti ve mutations of th e  Se r/Thr kinaseBub 1 pr e v en ted th e  de la y  in p rogression thro ugh mitosi su po n treatmen t  of  c ells of  the ye ast S .  cerevi siae with  microtub ul e-de s t abi lizing dru gs, whic h led tot he id e nt ifica tio n of B ub 1 a s a m itotic che ckpoi nt pro te in [Ro berts  B  T et al ., Mol. Cell Biol., 14,  8282,  1994 ].A numberofr ece nt public atio ns provide  ev ide nce t hat Bub1play s  m ult i ple r oles during mi t os isw h ic h, have bee n r evi ewedbyE lowe [ Elow e S, Mol. Cell. B i ol. 31, 3085,2011 . Inpar t icul ar , Bub1 is oneofth e first mi to tic checkpo int prot ei n s tha t bind s to t he kine t o ch o res of  dup lic ated chro mos om e s and p ro ba b ly
ochores are_present and_generates a wait-signal to_give the_dividing_cell the_time_to ensure that_each kinetochore is_attached to a spindle_pole, and to_correct_attachment errors. Thus the mitotic checkpoint prevents a mitotic cell from completing cell division_with_unattached or_erroneously_attached_chromosomes [Suijkerbuijk S J and_Kops G J, Biochem. Biophys._Acta 1786,_24, 2008; Musacchio A and Salmon E D,_Nat._Rev. Mol. Cell._Biol. 8, 379, 2007]. Once all kinetochores are attached_with the mitotic spindle poles in_a correct bipolar_(amphitelic)_fashion,_the checkpoint is satisfied_and the cell enters anaphase and_proceeds through mitosis.
The mitotic checkpoint is_established by a complex network of a_number of essential proteins, including members_of the MAD (mitotic arrest_deficient, MAD_1-3) and Bub (Budding uninhibited_by benzimidazole, Bub_1-3) families,_Mps1 kinase, cdc20,_as well as other components [reviewed_in Bolanos-Garcia V_M and Blundell T L, Trends_Biochem._Sci. 36, 141,_2010],_many_of these_being over-expressed in_proliferating_cells (e.g._cancer_cells) and tissues [Yuan B et_al.,_Clin. Cancer Res. 12, 405, 2006]. The_major function of an_unsatisfied_mitotic checkpoint is to_keep the anaphase-promoting complex/cyclosome (APC/C)_in an inactive state. As soon_as the_checkpoint gets_satisfied the APC/C ubiquitin-ligase targets cyclin B and securin for proteolytic_degradation leading to separation of the_paired chromosomes and exit_from mitosis.
Inactive_mutations_of the Ser/Thr_kinase_Bub1 prevented_the delay in progression through mitosis upon_treatment of_cells of the yeast S. cerevisiae_with microtubule-destabilizing drugs, which_led_to the identification of Bub1 as_a mitotic checkpoint protein [Roberts B_T et al., Mol. Cell_Biol.,_14,_8282, 1994]. A number of_recent publications provide evidence that Bub1_plays multiple roles_during mitosis which, have been reviewed by_Elowe_[Elowe S, Mol. Cell. Biol. 31,_3085,_2011. In particular, Bub1 is one_of_the_first mitotic checkpoint proteins that_binds to the kinetochores of duplicated_chromosomes and probably