1. EBV protein EBNA2 interacts with the cellular protein CBF1, converting it from a transcriptional repressor to an activator. This mimics the interaction between the Notch intracellular domain (NICD) and CBF1.
2. Both EBNA2 and NICD bind to the repression domain of CBF1, displacing a corepressor complex that includes proteins like SIN3 and HDACs. They also recruit coactivators through their own activation domains.
3. Binding of EBNA2 and NICD to CBF1 relieves repression and activates transcription of target genes. Mutational studies show their interactions with CBF1 and recruitment of cofactors like SIN
1. EBV protein EBNA2 interacts with the cellular protein CBF1, converting it from a transcriptional repressor to an activator. This mimics the interaction between the Notch intracellular domain (NICD) and CBF1.
2. Both EBNA2 and NICD bind to the repression domain of CBF1, displacing a corepressor complex that includes proteins like SIN3 and HDACs. They also recruit coactivators through their own activation domains.
3. Binding of EBNA2 and NICD to CBF1 relieves repression and activates transcription of target genes. Mutational studies show their interactions with CBF1 and recruitment of cofactors like SIN
1. EBV protein EBNA2 interacts with the cellular protein CBF1, converting it from a transcriptional repressor to an activator. This mimics the interaction between the Notch intracellular domain (NICD) and CBF1.
2. Both EBNA2 and NICD bind to the repression domain of CBF1, displacing a corepressor complex that includes proteins like SIN3 and HDACs. They also recruit coactivators through their own activation domains.
3. Binding of EBNA2 and NICD to CBF1 relieves repression and activates transcription of target genes. Mutational studies show their interactions with CBF1 and recruitment of cofactors like SIN
S# $iane %aywar& Viral Oncology Program, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of edicine, C!" #$%, &'($ Orleans Street, "altimore, ) *&*#&, US+ Abstract 'e !otc signaling "atway in(l)ences cell (ate &ecisions* "roli(eration +ers)s &i((erentiation an& cell s)r+i+al# Vir)ses ,ot )tili-e an& mani")late te &i((erentiation state o( in(ecte& cells* "romote or ,loc. cell cycling an& em"loy a +ariety o( mecanisms to e+a&e innate cell)lar anti/+iral res"onses an& "romote cell s)r+i+al# 0n ligt o( tese commonalities* it is "era"s not s)r"rising tat se+eral +ir)ses a+e ta""e& into te !otc "atway to a&+ance teir own li(e cycles# 'is (irst ,ecame a""arent (rom st)&ies sowing targeting o( 1"stein/Barr +ir)s "roteins to te n)clear e((ector o( !otc signaling CS2 (CB3145B67.)# 8ore recently te 9a"osi:s sarcoma/ associate& er"es+ir)s 5'; "rotein as ,een (o)n& to ,in& CS2# !otc "atway interactions a+e also ,een &escri,e& (or a&eno+ir)s SV40 an& )man "a"illoma +ir)s# 'is re+iew (oc)ses on te er"es+ir)s "rotein interactions wit te !otc "atway an& te insigts tat tese interactions a+e "ro+i&e&# < 2004 1lse+ier 2t&# ;ll rigts reser+e&# Key,ords- !otc "atway= 1"stein/Barr +ir)s= 9a"osi:s sarcoma er"es+ir)s 1. Introduction 1"stein/Barr Vir)s (1BV) an& 9a"osi:s sarcoma/associate& er"es+ir)s (9S%V) are )man er"es+ir)ses wit 1BV ,elonging to te gamma 1 lym"ocry"to+ir)s gro)" an& 9S%V te gamma 2 ra&ino+ir)s gro)"# ; caracteristic o( er"es+ir)ses is teir a,ility to set )" a latent state &)ring wic only a s),set o( te +iral genes are e>"resse& an& te in(ecte& cell s)r+i+es to esta,lis a li(e/long in(ection in te ost ?1*2@# %er"es+ir)ses also )n&ergo a lytic re"licati+e "ase in wic te in(ecte& cell &ies an& te +irions "ro&)ce& s"rea& te in(ection to nai+e cells an& new osts# 2ytic re"lication ta.es "lace in cells tat are growt arreste& ?3@# 1BV esta,lises latency in B cells an& it is te latency 1B!;2 an& 1B!;3 "roteins tat interact wit CB31an& "romote B cell "roli(erati+e res"onses# 1BV can also in(ect e"itelial cells were te lytic +ers)s latent o)tcome a""ears to ,e more &elicately ,alance&# 'e latency B;5' enco&e& "roteins 568S an& 59/B;530 are not well/caracteri-e& ,)t teir +..reviations- 1BV* 1"stein/Barr +ir)s= 9S%V* 9a"osi:s sarcomaassociate& er"es+ir)s= 1B!;2* 1"stein/Barr +ir)s n)clear antigen 2= %6V* )man "a"illoma +ir)s= ;&V* a&eno+ir)s= SV40* simian +ir)s 40= !otc0C* intracell)lar &omain o( !otc= CS2* < "romoter/,in&ing (actor* S)""ressor o( airless= 2ag/1= S906* S.i/interacting "rotein= 2861* latency mem,rane "rotein 1= 5';* re"lication an& transcri"tion acti+ator= B;5'* "am%0/; rigtwar& transcri"ts 'el#A +1/410/9BB/2B48= (a>A +1/410/B02/6802# /0mail address- &aywar&CDmi#e&) (S#$# %aywar&)# transcri"ts are igly e>"resse& in e"itelial cells an& tese "roteins may mo&i(y !otc acti+ity in te e"itelial setting ?46@# 9S%V esta,lises latency in B cells an& also in(ects en&otelial cells# 0n contrast to 1BV* 9S%V a""ears to rely "rimarily on mani")lation o( te Ent &e+elo"mental "atway to "romote "roli(erati+e res"onses ?7*8@# 0t is te 9S%V lytic cycle reg)lator 5'; tat interacts wit CB31 ?9*10@# 2. EBV EBNA2 interaction with CBF1 1B!;2 is a transcri"tional transacti+ator tat is one o( te (irst +iral genes e>"resse& a(ter 1BV in(ection o( B cells an& is essential (or 1BV immortali-ation o( B cells in +itro ?11*12@# 1B!;2 &oes not ,in& $!; &irectly ,)t reF)ires interactions wit cell "roteins (or "romoter targeting# 5egions o( te 1BV latency "romoters reF)ire& (or 1B!;2 res"onses were ma""e& an& (o)r gro)"s )sing sligtly &i((erent strategies i&enti(ie& te 1B!;2/interacting "rotein as CB3145B67. ?1316@# CB31 (C"/,in&ing (actor 1) is te )man omolog o( $roso"ila s)"ressor o( airless (S)%)* m)rine recom,ination/,in&ing "rotein 7 .a""a (5B67_) an& C1 elegans 2ag/1# 'ese "roteins are o(ten re(erre& to as CS2 (or CB31* S)% an& 2ag/1# ;t te time o( tis i&enti(ication* CS2 "roteins were .nown (rom genetic e>"eriments to ,e &ownstream e((ectors o( !otc signaling# %owe+er* te mecanisms ,y wic te !otc signal le& to canges in gene reg)lation in te n)cle)s were not well/)n&erstoo&# 1044/B79G4H see (ront matter < 2004 1lse+ier 2t&# ;ll rigts reser+e&# &oiA10#10164D#semcancer#2004#04#018 388 S1)1 Hay,ard 2 Seminars in Cancer "iology &3 4*$$35 #%67#8' 3ig# 1# (;) Scematic o( te CB31 core"ressor com"le># 'e locations o( te S906* S85' an& C05/,in&ing sites relati+e to te CB31 re"ression &omain are in&icate&# 'e same m)tations tat "re+ent S85' ,in&ing to CB31 also "re+ent C05 ,in&ing ?21*22@# (B) Scematic o( te interactions in te acti+ation com"le># 'e similarity o( targeting o( !otc0C an& 1B!;2 is igligte&# 0nteractions wit S906 occ)r tro)g te an.yrin re"eat &omain (!otc0C) an& Conser+e& 5egion B (C5B* 1B!;2)# 0nteractions wit te re"ression &omain )tili-e te 5;8 (!otc0C) an& C56 (1B!;2) &omains# 'ranscri"tional acti+ation o( target genes occ)rs tro)g te com,ination o( loss o( re"ression an& te "ositi+e e((ects o( te acti+ation &omain (;C')# !* amino termin)s= C* car,o>y termin)s# St)&ies wit 1B!;2 "ro+i&e& some insigt an& re+eale& tat 1B!;2 mimic.e& !otc0C ()nction to a remar.a,le &egree# 'ransient assays )sing Ial4/CB31 constr)ctions re+eale& tat CB31 ()nctione& as a transcri"tional re"ressor# CB31 me&iates re"ression tro)g &irect contacts wit te ,asal transcri"tion macinery ?17@ an& tro)g cromatin remo&eling# 'e CB31 re"ressor com"le> incl)&es S85'4!Co5* %$;C1* %$;C2* S;630* C05 an& S906 ?1822@# 0n te core"ressor com"le>* S906 ,in&s to te car,o>y/terminal 50$/2 &omain o( S85' an& along wit S85' is im"ortant (or n)clear entry o( CB31 ?21@ (3ig# 1;)# S906 also interacts wit mSin3; ?19@ an& tis along wit te (act tat S;630 is "art o( te mSin3 com"le> im"lies tat mSin3 is also "resent in te com"le># 5ecently 80!'4S%;56 as ,een i&enti(ie& as a CB31 interacting core"ressor wose ,in&ing is (acilitate& ,y S906 ?23*24@# S%;56 ,in&s S85' ,)t as also ,een (o)n& to associate wit te !)5$ com"le> ?2B@# 1B!;2 ,in&s to te re"ression &omain o( CB31* con+erting CB31 into a transcri"tional acti+ator ?26@# 'is con+ersion is a two/ste" "rocess as &emonstrate& )sing 1B!;2 m)tants# ;n 1B!;2 ca"a,le o( ,in&ing CB31 ,)t lac.ing te acti+ation &omain was a,le to relie+e re"ression ,y &is"lacing te CB31core"ressor com"le># 'ranscri"tional )"reg)lation reF)ire& te "resence o( te 1B!;2 acti+ation &omain wic recr)its coacti+ator "roteins ?26*27@# !otc10C an& !otc20C "ro+e& to interact wit te same &omain o( CB31 an& again tere was e+i&ence (or te o)tcome ,eing te s)m o( relie( o( re"ression "l)s acti+ation ?18*28*29@# 'e contacts ma&e ,y 1B!;2 on te CB31 re"ression &omain a""ear to ,e &is"lace& C/terminally relati+e to tose ma&e ,y !otc0C an& "oint m)tations in CB31 can &iscriminate ,etween 1B!;2 an& !otc0C/,in&ing# 3or e>am"le* a tri"le alanine s),stit)tion o( 92V 249/2B1 in CB31 a,olises !otc10C an& !otc20C/,in&ing ,)t &oes not a((ect 1B!;2/,in&ing ?29@ wile s),stit)tions at 2326 an& J333 &iminis 1B!;2 interaction ,)t not !otc10C/,in&ing ?30@# 'e mecanism o( !otc0C an& 1B!;2 &is"lacement o( te CB31 core"ressor com"le> a""ears to ,e i&entical (3ig# 1B)# 0n eac case a&Dacent &omains ma.e contact wit CB31 an& S906 to &is"lace S85'# S906 is "artic)larly interesting as it is a com"onent o( te core"ressor com"le> an& it is also a com"onent o( te acti+ation com"le># $irect com"etition (or ,in&ing to S906 as ,een &emonstrate& (or S85' an& 1B!;2 an& (or S85' an& !otc0C ?19*20@# Similarly* ,in&ing o( S85' to CB31 is m)t)ally e>cl)si+e wit ,in&ing to 1B!;2 or !otc0C ?18*19@# 'e 5;8 &omain o( !otc0C is te maDor contact wit CB31 ?28*29*31@ wile te an.yrin re"eats ,in& S906 ?20@# Conser+e& 5egion B o( 1B!;2 ,in&s S906 an& Conser+e& 5egion 6 ,in&s CB31# ; m)tation witin Conser+e& 5egion 6 tat a,olises 1B!;2 ,in&ing to CB31 (EE323S5) com"letely a,olises 1B!;2 transacti+ation ?32*33@ an&* wen incor"orate& into te +ir)s* m)tation o( tese two resi&)es res)lts in a non/immortali-ing 1BV ?34@# 8)tants in Conser+e& 5egion B s)c as 00307 tat are im"aire& (or S906 interaction are eF)ally im"aire& (or transacti+ation ()nction ?19@# 0ntro&)ction o( &eletions tat s"an C5B o( 1B!;2 into te 1BV genome le& to m)tant +ir)s tat eiter (aile& to immortali-e B cells in +itro or res)lte& in B cell colonies tat grew less well tan wil&/ty"e +ir)s immortali-e& controls S1)1 Hay,ard 2 Seminars in Cancer "iology &3 4*$$35 #%67#8' 389 ?3B@# 0nterestingly* it was note& in te latter case tat te cells o+ere>"resse& te m)tant 1B!;2 "rotein# ; similar sit)ation is (o)n& wit !otc10C were m)tation o( two amino aci&s in te (o)rt an.yrin re"eat a,olise& S906 interaction* se+erely im"aire& transacti+ation o( a re"orter containing CB31/,in&ing sites ?20@ an& a,olise& te a,ility o( !otc to ini,it myogenesis ?36@# ')s* 1B!;2 an& !otc0C eac reF)ire contacts wit S906 as well as CB31 (or e((ecti+e acti+ation o( "romoters containing CB31/,in&ing sites# *1&1 od9lation of /":+* transcriptional responses 'ere are ()rter "arallels ,etween 1B!;2 an& !otc0C in te ways in wic transcri"tional acti+ation tro)g CB31 is mo&i(ie&# 'e acti+ation &omains o( tranacti+ator "roteins ,in& coacti+ators tat mo&i(y cromatin str)ct)re tro)g istone acetylase acti+ity an& ma.e contacts wit te ,asal transcri"tional macinery# 'e acti+ation &omain o( 1B!;2 ,in&s core transcri"tional (actors ?37*38@* "300* 6C;3 an& CB6 ?27@ an& a coacti+ator* "100 tat interacts wit '3001 ?39@# 0n a&&ition transacti+ation is a)gmente& ,y ,in&ing to te 1BV enco&e& 1B!;/26 "rotein ?40*41@ an& ,y interactions wit te SE04S!3 com"le> ?42@ an& te $1;$/,o> "rotein $61034Iemin3 ?43@# 'e !otc0C acti+ation &omain ,in&s IC!4* 6C;3 an& "300 ?4446@ an& ()ll transcri"tional acti+ation ,y !otc reF)ires te )man omolog o( $roso"ila 8astermin&* 8;821 wic ,in&s to te an.yrin re"eat &omain o( !otc an& also recr)its CB64"300 ?4749@# 5es"onses to !otc an& 1B!;2 are igly concentration/&e"en&ent an& negati+e reg)lation o( te acti+ity o( te CB31 com"le> occ)rs tro)g mo&)lation o( CB31 $!; ,in&ing# 1BV enco&es tree relate& "roteins generate& tro)g gene &)"lication* 1B!;3;* 3B an& 3C# 'ese "roteins com"ete wit 1B!; 2 (or ,in&ing to CB31 ?B0B3@# 'e CB311B!;3 com"le> &oes not ,in& to $!; ?B4*BB@ an& so transcri"tional acti+ation is ,loc.e& ,ot ,y loss o( access to CB31 an& ,y loss o( CB31 "romoter targeting# 'e "ositi+e reg)lation o( 1B!;2 ,y 1B!;/26 ,in&ing an& te ,alancing negati+e reg)lation ,y te 1B!;3 (amily "laces 1B!;2 acti+ity largely )n&er +iral control an& at te le+el o( te CB31 com"le> (3ig# 2)# !otc0C acti+ity is also reg)late& in "art ,y loss o( CB31 ,in&ing# 'e 208 "rotein 9yo'2 was i&enti(ie& in a yeast two/y,ri& screen as a CB31/interacting "rotein an& sown to "re+ent $!; ,in&ing ,y CB31 ?B6@# 80!'4S%;56 antagoni-es !otc0C ,in&ing to CB31 ?23*24@# K+erall* owe+er* !otc0C ()nction may ,e reg)late& less at te "oint o( CB31 com"le> an& more tro)g "rocesses s)c as &i((erential e>"ression o( !otc ligan&s* rece"tor recycling an& "rotein t)rno+er ?B7*B8@# 'e mecanistic concor&ance ,etween te interactions o( 1B!;2 an& !otc0C wit te CB31 re"ressor com"le> is re(lecte& in te a,ility o( te two "roteins to acti+ate te same CB31/reg)late& genes in re"orter assays ?B9@* 1BV latency "romoters (wit te e>ce"tion o( 2861) ?60@ an& a((ect e>"ression o( te same cell)lar genes# 1>am"les o( te latter are )"reg)lation o( 3ig# 2# 0ll)stration o( 1BV mo&)lation o( te CB31 com"le># CB31 ,in&s to te seF)ence I'III;; ?143*144@# 1B!;2 )ses CB31 (or "romoter targeting an& mimicry o( !otc signaling# 'e 1B!;3 (amily o( "roteins negati+ely reg)late 1B!;2 acti+ity ,y ,in&ing to CB31 an& "re+enting CB31 (rom ,in&ing $!; ?B4*BB@ an& ,y com"eting wit 1B!;2 (or CB31/,in&ing ?B0*B3@# 568S "re+ents 1B!;2 &is"lacement o( te core"ressor com"le> ?4@# 1B!;/26 interaction wit 1B!;2 increases 1B!;2 acti+ity ?40*41@# B;'3 ?61@ an& C$21 ?60@ an& &ownreg)lation o( te 0g enancer ?60*62@# !otc0C me&iates e((ects tat are in&e"en&ent o( CB31 ?636B@ an& 1B!;2 can target "romoters tro)g 6)#1 ?66*67@# 1B!;2 an& !otc a+e no "rimary seF)ence omology an& eac a+e s"eci(ic "rotein "artners# %owe+er* CB31 targeting a""ears to ,e a &ominant ()nction (or ,ot "roteins to te e>tent tat !otc0C an& 1B!;2 can ,e "artially e>cange& in some ()nctional assays# !otc0C "re+ents te &i((erentiation o( C2C12 myo,lasts into myot),)les an& 1B!;2 as a similar e((ect ?68@# 0n tose cells con&itionally e>"ressing 1B!;2* !otc10C co)l& "artially com"ensate (or loss o( 1B!;2# 0n one st)&y* !otc10C s)""orte& cell "roli(eration (or a sort "erio& in te "resence o( an in&e"en&ently e>"resse& 2861 gene ,)t tere was a &e(icit in )"reg)lation o( c/8yc an& te cells &ie& a(ter se+eral &ays ?69@# 0n a secon& st)&y* iger le+els o( !otc10C resc)e& cell growt alto)g te cells e>"an&e& more slowly tan in te "resence o( 1B!;2 ?70@# 2ym"o,lastoi& cell lines are &e"en&ent on 2861 (or growt an& te ina,ility o( !otc0C to e((ecti+ely )"reg)late 2861 is consistent wit te 2861 "romoter a+ing more com"le> reg)lation tan sim"le CB31 tetering# 1B!;2 also ,in&s to a 6)#1 site in te 2861 "romoter ?66*67@* an& )niF)ely* 1B!;3 co/o"erates wit 1B!;2 rater tan antagoni-ing 1B!;2 acti+ation o( 2861 e>"ression ?71*72@# *1*1 /":+* and cell s9rvival 0n lym"o,lastoi& B cell lines e>"ressing 1B!;2 ()se& to te ormone ,in&ing &omain o( te estrogen rece"tor* wit&rawal o( estrogen res)lts in cessation o( cell growt an& a signi(icant "ro"ortion o( te cells &ie ,y a"o"tosis ?73@# 2oss o( e>"ression o( 1B!;2/reg)late& genes s)c as cell)lar c/myc* cyclin $2 an& c&.4 ?73*74@ an& 1BV 2861 an& 2862 ('6) ?7B@ contri,)te s),stantially to tis o)tcome# 2861* wic ()nctionally mimics constit)ti+e t)mor necrosis (actor rece"tor signaling* "romotes cell s)r+i+al 390 S1)1 Hay,ard 2 Seminars in Cancer "iology &3 4*$$35 #%67#8' tro)g acti+ation o( !3/_B* Bcl/2 an& ;20 ?7683@ an& ;.t acti+ity ?84@# 2862; "ro+i&es a cell s)r+i+al ()nction also "artially tro)g acti+ation o( ;.t ?8B87@# $ata o,taine& )sing emo"oietic "rogenitor cells (rom !otc antisense transgenic mice in&icates tat !otc1 can reg)late !3/_B acti+ity ?88@ an& e+i&ence as ,een "resente& (or !otc10C/in&)ce& )"reg)lation o( Bcl/2 an& 60394;.t acti+ity in ' cells ?89@# ; com"onent o( te co/o"erati+e e((ect o( !otc1 on trans(ormation ,y )man "a"illoma +ir)s (%6V) 16 an& 17 is anti/a"o"totic an& me&iate& tro)g ;.t ?90@# !otc10C also as te a,ility to "rotect against 'C5/in&)ce& a"o"tosis tro)g a &irect interaction wit te n)clear ormone rece"tor (amily mem,er !)r77 ?91@# !)r77 acts ,ot as a transcri"tion (actor ?92@ an& as a me&iator o( a"o"tosis# 0n te latter ca"acity* !)r77 translocates to te cyto"lasm an& targets mitocon&ria to in&)ce cytocrome C release ?93@# 'e anti/!)r77 acti+ity o( !otc10C "rom"te& an e+al)ation o( te anti/a"o"totic ca"a,ilities o( 1B!;2# Lsing Sin&,is +ir)s in(ection to in&)ce !)r77 syntesis an& a"o"tosis* it was &emonstrate& tat 1B!;2 co)l& li.ewise ,in& to !)r77 an& "rotect against !)r77/in&)ce& cell &eat ?94@# 'e mecanism o( "rotection was i&entical# Bin&ing o( eiter !otc10C or 1B!;2 "re+ente& mitocon&rial targeting o( !)r77 in res"onse to a"o"totic stim)li an& !)r77 remaine& in te n)cle)s# *1#1 Cell cycle arrest- /":+* and KSHV !T+ !otc me&iates cell (ate &ecisions an& can "romote &i((erentiation as well as "roli(eration# 0n "rimary .eratinocytes !otc10C ca)ses growt s)""ression tro)g in&)ction o( "21 ?9B@ an& a similar o,ser+ation as ,een ma&e a(ter !otc o+ere>"ression in small cell l)ng cancer cells ?96@# !otc10C e>"ression in te cic.en B cell line $'40 also in&)ces I1 cell cycle arrest ?97@# 'e &i((erentiation res"onse to !otc can ,e tiss)e/s"eci(ic or relate& to a com,ination o( te &e+elo"mental stage o( te cell an& te "resence or a,sence o( mo&)lators o( signal intensity# Eile 1B!;2 is clearly growt "roli(erati+e in te conte>t o( an 1BV in(ection* e>"ression o( 1B!;2 in te a,sence o( te mo&)lating 1B!;3 "roteins res)lts in retar&ation o( cell growt an& "21 in&)ction# 1B!;2 e>"ression in naso"aryngeal carcinoma cells* osteosarcma L2KS* Vero an& 293 cells le& to "21 in&)ction me&iate& tro)g "B3 an& retar&ation o( cell growt ?98@# B)r.itt lym"oma B cells maintain ty"e 0 latency an& &o not e>"ress 1B!;2 or te 1B!;3 "roteins# Con&itional e>"ression o( 1B!;2 in B)r.itt lym"oma cells res)lte& in growt arrest an& in&)ce& en&ogeno)s inter(eron al"a ?99*100@# 1>ogeno)s e>"ression o( 1B!;2 in ;.ata B)r.itt lym"oma cells in&)ce& te 1BV lytic cycle* wic ta.es "lace in I1 arreste& cells* an& tis in&)ction reF)ire& te CB31 interacting &omain o( 1B!;2 ?101*102@# 0n 1BV "ositi+e lym"o,lastoi& cells con&itional o+ere>"ression o( 1B!;3; li.ewise ca)se& I04I1 growt arrest ?B3@# ')s* e+en in B cells* te res"onse to 1B!;2 is igly &e"en&ent on te le+el o( "rotein a+aila,le (or CB31 interaction# 9S%V in(ects ,ot B cells an& en&otelial cells# 'e 9S%V 5'; "rotein is te .ey +iral "rotein reg)lating te switc (rom latent to lytic +iral re"lication ?103*104@# 5'; is a transcri"tional transacti+ator tat ,in&s &irectly to $!; ,)t also targets +iral "romoters in&irectly ,y tetering to cell)lar transcri"tion (actors ?10B*106@# Kne o( te cell)lar "artners (or 5'; is CB31 ?9@# 'e regions o( CB31 necessary (or 5'; ,in&ing incl)&e te re"ression &omain tat is also targete& ,y 1B!;2 an& !otc0C# ')s* 5'; a""ears to ,e )sing te same mecanism to acti+ate CB31 containing "romoters# ; &i((erence ,etween 1BV an& 9S%V in teir mimicry o( !otc is tat 1BV* tro)g 1B!;2* )ses te "atway (or +iral latent in(ection wile te 9S%V 5'; "rotein is te .ey reg)lator o( te lytic cycle an& 9S%V latent in(ection can ,e esta,lise& in CS2 n)ll cells ?10@# 'e &i((erent )se o( te !otc "atway may ,e relate& in "art to te cell tro"ism o( 9S%V# !otc ()nction is critical to +asc)lar &e+elo"ment ?107*108@ an& in en&otelial cells !otc signaling "romotes cell &i((erentiation ?109@# 'e lytic re"licati+e "ase o( a er"es+ir)s li(e cycle ta.es "lace in cells tat are arreste& in te cell cycle an& 9S%V enco&es lytic "roteins tat (acilitate cell cycle arrest ?110@# 'o &ate 5'; as only ,een sown to acti+ate 9S%V genes tro)g CB31 ,)t i( 5'; also targets CB31/reg)late& en&otelial cell genes* te o)tcome so)l& ,e com"ati,le wit a lytic re"licati+e en+ironment (or te +ir)s# 3. EBNA2 function in EBV biology 1BV immortali-es B cells in c)lt)re to generate contin)ally "roli(erating B lym"o,lastoi& cell lines# 1B!;2 an& te 1B!;3; an& 3C "roteins are essential (or tis "rocess as is 2861 ?111@# 1B!;2 clearly stim)lates B cell s)r+i+al an& growt "roli(eration in te setting o( 1BV in(ection# 3)rter* as alrea&y esta,lise&* 1B!;2:s main mecanism o( action is as a mimic o( !otc0C# 0t as not ,een clear ow to integrate tese (acts wit wor. &emonstrating tat a &ominant ()nction o( !otc10C in emato"oiesis is to in&)ce common lym"oi& "rogenitors to a&o"t a ' cell (ate at te e>"ense o( B cell &e+elo"ment ?11211B@# ;lto)g te role o( !otc in te B cell com"artment remains incom"letely )n&erstoo&* recent o,ser+ations allow s"ec)lation on te ways in wic te 1B!;2 )s)r"ing o( !otc ()nction may s)stain a li(e/long 1BV in(ection in te ost# 3irstly* tere is e+i&ence tat !otc signaling increases te (ormation o( emato"oietic stem cells# 7agge&1 is e>"resse& on ,one marrow stoma an& on stromal cell lines an& coc)lt)re o( m)rine marrow "rec)rsors wit 7agge&1 increase& te (ormation o( "rec)rsor cell "o")lations ?116*117@# Ksteo,lastic cells also e>"ress 7agge&1 an& increase& e>"os)re to osteo,lasts a)gments "rimati+e aemato"oietic cell growt in a !otc/&e"en&ent manner ?118@# 1B!;2/&ri+en B cell "roli(eration may t)s ,e reca"it)lating a "rec)rsor stem S1)1 Hay,ard 2 Seminars in Cancer "iology &3 4*$$35 #%67#8' 391 cell res"onse# 'is "roli(eration is to)gt to ,e im"ortant in e>"an&ing te in(ecte& cell "o")lation a(ter "rimary 1BV in(ection to "ermit esta,lisment o( a li(e/long latency in te B cell com"artment# 0n ealty 1BV/"ositi+e in&i+i&)als* e>"ression o( 1B!;2 is restricte& to nai+e 0g$+ B cells in secon&ary lym"oi& tiss)e ?119*120@# 0g$+ B cells are concentrate& in te marginal -one o( germinal centers# 'ransgenic mice tat are con&itionally &e(icient (or CB31 in B cells sow a selecti+e loss o( marginal -one B cells wit loss o( CB31* im"licating !otc signaling in te &e+elo"ment o( tese cells ?121@# 5ein(orcing tis o,ser+ation* trans(er o( 80!'/&e(icient s"lenic B cells into reci"ient mice le& to "re(erential &i((erentiation into marginal -one B cells ?24@# 80!'4S%;56* a CB31 interactor tat antagoni-es !otc acti+ity* as ig e>"ression in mo)se (ollic)lar B cells an& low e>"ression in marginal -one B cells# !otc2 is te rele+ant !otc (amily mem,er as !otc2 e>"ression is ig in marginal -one B cells ?122@ an& ()rter* con&itional &eletion o( !otc2 in mice res)lte& in a &e(iciency in marginal -one B cells ?123@# 'e (act tat 1B!;2 is selecti+ely e>"resse& in te same com"artment o( te germinal center were !otc2 e>"ression is essential (or B cell &e+elo"ment strengtens te conce"t tat 1BV is )sing 1B!;2 as a +irally controlle&* constit)ti+e !otc s)rrogate# . !he EBV BA"!s 'e 1BV Bam%0/; rigtwar& transcri"ts (B;5's) were (irst &escri,e& in naso"aryngeal t)mor tiss)es were tey are te most a,)n&ant +iral transcri"ts ?124*12B@# B;5's were s),seF)ently recogni-e& to ,e e>"resse& in all 1BV latently in(ecte& cells ?126130@# 'e alternati+ely s"lice& B;5' (amily o( 5!;s contain tree recogni-e& o"en rea&ing (rames# 0t as ,een &i((ic)lt to con+incingly &emonstrate e>"ression o( te "roteins enco&e& ,y tese 5!;s in 1BV/in(ecte& cells ,)t te "ro&)cts o( two o( te o"en rea&ing (rames* 568S an& 59/B;53K interact wit te !otc "atway wen e>"resse& e>ogeno)sly# 568S ()nctions in a way tat is reminiscent o( 80!'4S%;56# 568S ,in&s to C05 in te CB31 core"ressor com"le> an& me&iates re"ression wen e>"resse& as a Ial4/568S ()sion "rotein ?4@# 568S antagoni-es 1B!;2 ()nction in re"orter assays an& !otc10C ()nction in ,ot re"orter assays an& in a m)scle &i((erentiation assay ?4*B@# 568S a((ects te C05S906 interaction in a way tat "re+ents 1B!;24!otc10C (rom &is"lacing te core"ressor com"le># S906 (acilitates S%;56 ()nction an& t)s S906 is not only a .ey tetering "oint (or 1B!;24!otc0C ,in&ing ,)t also a .ey target (or negati+e mo&)lation o( teir acti+ity# 'e 1BV 59/B;530 "rotein was (o)n& to interact wit !otc4 in a yeast two/y,ri& assay ?6@# 59/B;530 contains a "otential signal "e"ti&e (or en&o"lasmic retic)l)m targeting an& interacts wit )n"rocesse& !otc4# 59/B;530 a""ears to "otentiate !otc ()nction# 'e B;5's are e>"resse& in circ)mstances in wic te 1B!;2 an& 1B!;3 "roteins are not syntesi-e& s)c as in e"itelial cell in(ection an& in 1BV/associate& t)mors in imm)nocom"etent in&i+i&)als# 0t is interesting tat tese transcri"ts so)l& enco&e ,ot a "ositi+e an& a negati+e !otc reg)lator an& tis re/em"asi-es te im"ortance o( signal mo&)lation (or !otc "atway res"onses# 'e e>istence o( te B;5's also s)ggests tat tere may ,e as yet )na""reciate& as"ects o( 1BV ,iology were mani")lation o( !otc signaling occ)rs# #. Adeno$irus% hu&an 'a'illo&a $irus and (V) Kter +ir)ses tat a+e interactions wit te !otc "atway are a&eno+ir)s (;&V)* %6V an& simian +ir)s 40 (SV40)# 'e (irst association wit ;&V came (rom te recognition o( a CB31(5B62!) ,in&ing site in te "0G "romoter ?131@# S),seF)ently ;&V 13S11; was sown to ,in& to CB31 an& to ,e ca"a,le o( acti+ating "romoters containing CB31/,in&ing sites in re"orter assays ?132@# 13S11; interaction reF)ire& CB31 seF)ences !/terminal to te CB31 re"ression &omain ,)t te mecanism o( action still a""ears to in+ol+e &is"lacement o( te S85' core"ressor com"le># 'e interactions ,etween !otc an& %6V an& !otc an& SV40 are co/o"erati+e in nat)re# !otc1 ,)t not !otc2 can &ownreg)late e>"ression o( te %6V 16417 genes in cer+ical cancer cells# 'e &ownreg)lation res)lts (rom s)""ression o( ;6/1 acti+ity an& increase& e>"ression o( te negati+e reg)lator 3ra1 ?133@# %6V16 16 an& 17 "roteins in t)rn )"reg)late !otc1 acti+ity tro)g increase& transcri"tion an& tro)g increase& e>"ression o( "resenilin/1 ?134@# 'ese o,ser+ations s)ggest te e>istence o( a (ee&/,ac. loo" to reg)late !otc acti+ity# 'e co/o"erati+ity ,etween !otc0C an& 16417 in trans(ormation assays as ,een s)ggeste& to &eri+e (rom an anti/a"o"totic ()nction me&iate& tro)g ;.t ?90*13B@# SV40 in(ection also transcri"tionally )"reg)lates e>"ression o( !otc1 ?136@# SV40 in(ection as ,een associate& wit )man mesotelioma ?137@# 0n )man mesotelial cells* te SV40/me&iate& increase in !otc1 acti+ity is necessary (or cell growt as treatment o( te cells wit a gamma/secretase ini,itor le& to I248 cell cycle arrest ?136@# *. Conclusion 'e a,ility o( !otc signaling to in(l)ence ,ot "roli(erati+e an& &i((erentiation res"onses ma.es tis "atway an attracti+e target (or +ir)ses wic are sensiti+e to te &i((erentiation state o( te cell# %6V an& SV40 ta" into te "atway ,y )"reg)lating e>"ression o( acti+ate& !otc wile 1BV* 9S%V an& ;&V enco&e "roteins tat ,in& to CB31 an& mimic as"ects o( !otc signaling# 1ac o( tese +ir)ses also as mecanisms to &ysreg)late cell cycle control# ;cti+ate& !otc signaling in a cell in wic cell cycle 392 S1)1 Hay,ard 2 Seminars in Cancer "iology &3 4*$$35 #%67#8' cec."oints a+e ,een ren&ere& ine((ecti+e esta,lises a s)sce"ti,ility to )nreg)late& growt# %6V* 1BV an& 9S%V are associate& wit )man cancers an& SV40 as ,een lin.e& to mesotelioma# 0n te cases o( %6V an& SV40/associate& cancers were te +iral "roteins )"reg)late !otc acti+ity* &r)gs &irecte& against !otc ()nction or "rocessing may a+e treatment +al)e i( a tera"e)tic win&ow e>ists in wic normal !otc signaling in te "atient can ,e s"are&# 9S%V targets CB31 &)ring te +iral lytic cycle# ;lto)g lytically 9S%V/in(ecte& cells are ,elie+e& to contri,)te to 9S%V/associate& t)morigenesis tro)g "aracrine signaling* tere are oter "atways acti+ate& in te lytic cycle tat wo)l& seem to "ro+i&e more attracti+e anti/+iral targets# 1BV as in+este& ea+ily in mani")lation o( !otc signaling wit 1B!;2* 1B!;3;* 3B an& 3C* 1B!;/26* 59/B;530 an& 568S all ,eing &irecte& towar&s te CB31 com"le># 'ese "roteins are e>"resse& in 1BV/associate& t)mors in imm)nocom"romise& "atients ?138141@# ; cell/"ermea,le 1B!;2 "e"ti&e tat ,loc.s te 1B!;2CB31 interaction can "re+ent 1BV immortali-ation o( "rimary B cells in +itro ?142@ "ro+i&ing "roo( o( "rinci"le tat targeting te !otc "atway may a+e clinical "otential against 1BV/associate& &isease# 'ese 1B!;s are also transcri,e& in secon&ary lym"oi& tiss)e in ealty sero"ositi+e in&i+i&)als ?119@ an& it is interesting to consi&er weter s)ccess()l targeting o( tis "atway co)l& eliminate li(e/long 1BV in(ection# Ac+nowledge&ents 'is wor. was s)""orte& in "art ,y grant 537 C;4224B (rom te !ational Cancer 0nstit)te#
Detection of Seepage Patterns Direction in The Bajulmati Dam, Banyuwangi, Indonesia Using Geoelectrical Method, Schlumberger and Dipole Dipole Configuration