RB1

S Wikipedije, slobodne enciklopedije
RB1
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1AD6, 1GH6, 1GUX, 1H25, 1N4M, 1O9K, 1PJM, 2AZE, 2QDJ, 2R7G, 3N5U, 3POM, 4ELJ, 4ELL, 4CRI

Identifikatori
AliasiRB1
Vanjski ID-jeviOMIM: 614041 MGI: 97874 HomoloGene: 272 GeneCards: RB1
Lokacija gena (čovjek)
Hromosom 13 (čovjek)
Hrom.Hromosom 13 (čovjek)[1]
Hromosom 13 (čovjek)
Genomska lokacija za RB1
Genomska lokacija za RB1
Bend13q14.2Početak48,303,744 bp[1]
Kraj48,599,436 bp[1]
Lokacija gena (miš)
Hromosom 14 (miš)
Hrom.Hromosom 14 (miš)[2]
Hromosom 14 (miš)
Genomska lokacija za RB1
Genomska lokacija za RB1
Bend14 38.73 cM|14 D3Početak73,421,113 bp[2]
Kraj73,563,262 bp[2]
Obrazac RNK ekspresije


Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija DNA binding
GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity
GO:0001105 transcription coactivator activity
transcription factor binding
phosphoprotein binding
kinase binding
GO:0001948, GO:0016582 protein binding
androgen receptor binding
identical protein binding
enzyme binding
ubiquitin protein ligase binding
importin-alpha family protein binding
disordered domain specific binding
GO:0001158 cis-regulatory region sequence-specific DNA binding
GO:0001078, GO:0001214, GO:0001206 DNA-binding transcription repressor activity, RNA polymerase II-specific
Ćelijska komponenta PML body
SWI/SNF complex
transcription regulator complex
Diobeno vreteno
cyclin/CDK positive transcription elongation factor complex
Hromatin
Jedro
Nukleoplazma
Rb-E2F complex
Biološki proces negative regulation of cell population proliferation
negative regulation of mitotic cell cycle
neuron apoptotic process
androgen receptor signaling pathway
chromatin remodeling
negative regulation of smoothened signaling pathway
negative regulation of protein kinase activity
cell morphogenesis involved in neuron differentiation
mitotic cell cycle checkpoint signaling
GO:0044324, GO:0003256, GO:1901213, GO:0046019, GO:0046020, GO:1900094, GO:0061216, GO:0060994, GO:1902064, GO:0003258, GO:0072212 regulation of transcription by RNA polymerase II
positive regulation of macrophage differentiation
cellular response to xenobiotic stimulus
negative regulation of cell cycle
negative regulation of DNA-binding transcription factor activity
transcription, DNA-templated
glial cell apoptotic process
regulation of cohesin loading
regulation of cell cycle
neuron maturation
Ćelijska dioba
GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated
GO:1990376 negative regulation of G1/S transition of mitotic cell cycle
positive regulation of mitotic metaphase/anaphase transition
GO:1903097, GO:1903098, GO:1903099 regulation of centromere complex assembly
enucleate erythrocyte differentiation
neuron differentiation
regulation of mitotic cell cycle
negative regulation of epithelial cell proliferation
skeletal muscle cell differentiation
sister chromatid biorientation
protein localization to chromosome, centromeric region
Ćelijski ciklus
striated muscle cell differentiation
Ras protein signal transduction
myoblast differentiation
GO:0022415 viral process
GO:0045996 negative regulation of transcription, DNA-templated
neuron projection development
digestive tract development
maintenance of mitotic sister chromatid cohesion
regulation of lipid kinase activity
GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II
hepatocyte apoptotic process
GO:0097285 Apoptoza
positive regulation of transcription regulatory region DNA binding
negative regulation of gene expression
regulation of cell growth
tissue homeostasis
GO:0009373 regulation of transcription, DNA-templated
G1/S transition of mitotic cell cycle
GO:1901227 negative regulation of transcription by RNA polymerase II
negative regulation of transcription involved in G1/S transition of mitotic cell cycle
GO:0031497, GO:0006336, GO:0034724, GO:0001301, GO:0007580, GO:0034652, GO:0010847 chromatin organization
aortic valve morphogenesis
negative regulation of inflammatory response
positive regulation of extracellular matrix organization
positive regulation of collagen fibril organization
negative regulation of myofibroblast differentiation
Ćelijska diferencijacija
negative regulation of cold-induced thermogenesis
negative regulation of protein serine/threonine kinase activity
negative regulation of tau-protein kinase activity
negative regulation of apoptotic signaling pathway
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)

NM_000321

NM_009029

RefSeq (bjelančevina)

NP_000312
NP_000312.2

NP_033055

Lokacija (UCSC)Chr 13: 48.3 – 48.6 MbChr 14: 73.42 – 73.56 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Retinoblastomski protein (pRb, Rb, RB ili RB1) je tumor-supresorski protein čija nefunkcionalnost uzrokuje nekoliko glavnih kancera.[5] Jedna od funkcija pRb je sprečavanje prekomjerne proliferacije ćelija, inhibiranjem progresije ćelijskog ciklusa sve dok ćelija nije spremna za diobu. Kad je ćelija spremna za podjelu, pRb se fosforilira, deaktivirajući je, i dopušta se ćelijskom ciklusu da napreduje. Također je regruter nekoliko enzima za remodeliranje hromatina, kao što su metilaze i acetilaze.[6]

pRb pripada porodici džepnih proteina, čiji članovi imaju džep za funkcionalno vezivanje drugih proteina.[7][8] Ako se onkogeni proteini, poput onih koje proizvode ćelije inficirane visokorizičnim tipovima ljudskog papiloma virusa, veže i inaktivira pRb, to može dovesti do raka. Gen RB je možda bio odgovoran za evoluciju višećelijskih oblika u nekoliko loza života, uključujući životinje.[9]

Ime i genetika[uredi | uredi izvor]

Kod ljudi, protein je kodiran genom RB1 koji se nalazi na hromozomu 13, tačnije, na sekvenci 13q14.1-q14.2. Ako oba alela ovog gena mutiraju u ranom životu, protein se inaktivira i rezultira razvojem retinoblastomakog raka, pa otuda i naziv pRb (p=protein). Ćelije mrežnjače se ne odmazuju i ne zamjenjuju, te su podvrgnute visokom nivou mutagenog UV-zračenja, pa se zato većina izlučivanja pRb-a javlja u njenom tkivu (ali je također dokumentirano kod određenih karcinoma kože kod pacijenata iz New Yorka i Novog Zrelanda gdje je količina UV zračenja znatno veća).

Uočena su dva oblika retinoblastoma: bilateralni, porodični i jednostrani, sporadični oblik. Pacijenti ovih bolesti imali su šest puta veću vjerojatnoću da će kasnije u životu razviti druge tipove raka.[10] Ovo je naglasilo činjenicu da se mutirani pRb mogao naslijediti i dati podršku za hipotezu o dva pogotka. Ovo navodi na zaključak da je samo jedan aktivni alel genski supresor tumora neophodan za njegovu funkciju (mutirani gen je recesivan), pa se prije pojave fenotipa raka dogosila takva mutacija. U porodičnom obliku, mutirani alel se nasljeđuje zajedno s normalnim. U ovom slučaju, ako bi ćelija održala samo jednu mutaciju u drugom "RB" genu, svi pRb u toj ćeliji bili bi nedjelotvorni u inhibiranju progresije ćelijskog ciklusa, dopuštajući ćelijama da se nekontrolirano dijele i na kraju postanu kancerogene. Nadalje, kako je jedan alel već mutiran u svim ostalim somatskim ćelijama, buduća učestalost karcinoma kod ovih osoba javlja se prema linearnoj kinetici.[11] Aktivni alel ne mora se podvrgnuti mutaciji per se, jer se u takvim tumorima često primjećuje gubitak heterozigotnosti (LOH) .

Međutim, u sporadičnom obliku, oba alela bi morala održati mutaciju prije nego što ćelija postane kancerogena. Ovo objašnjava zašto oboljeli od sporadičnog retinoblastoma nisu u povećanom riziku od raka kasnije u životu, jer su oba alela funkcionalna u svim drugim ćelijama. Buduća učestalost karcinoma u sporadičnim slučajevima pRb-a promatrana je polinomnom, kinetikom, ne baš kvadratnom, kako se očekivalo jer prva mutacija mora nastati normalnim mehanizmima, a zatim je LOH može duplicirati tumorskim progenitorima.

RB1 ortolozi [12] identificirani su i kod većine sisara, za koje su dostupni potpuni podaci o genomu.

RB/E2F-proteini porodice potiskuju transkripciju.[13]

Struktura označava funkciju[uredi | uredi izvor]

pRb je multifunkcionalni protein s mnogim mjestima vezanja i fosforilacija. Iako se njegova zajednička funkcija smatra vezanjem i potiskivanjem ciljeva E2F, pRb je vjerovatno višenamjenski protein jer se veže na najmanje 100 drugih proteina.[14]

pRb ima tri glavne strukturne komponente: karboksi-kraj, "džepnu" podjedinicu i amino-kraj. Unutar svakog domena postoje različita mjesta vezivanja proteina, kao i ukupno 15 mogućih mjesta fosforilacije. Općenito, fosforilacija uzrokuje zaključavanje među domenima, što mijenja konformaciju pRb i sprječava vezanje za ciljne proteine. Različita mjesta mogu se fosforilirati u različito vrijeme, što dovodi do mnogih mogućih konformacija i vjerovatno mnogih funkcija/nivoa aktivnosti.[15]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 928 aminokiselina, a molekulska težina 106.159 Da.[16].

1020304050
MPPKTPRKTAATAAAAAAEPPAPPPPPPPEEDPEQDSGPEDLPLVRLEFE
ETEEPDFTALCQKLKIPDHVRERAWLTWEKVSSVDGVLGGYIQKKKELWG
ICIFIAAVDLDEMSFTFTELQKNIEISVHKFFNLLKEIDTSTKVDNAMSR
LLKKYDVLFALFSKLERTCELIYLTQPSSSISTEINSALVLKVSWITFLL
AKGEVLQMEDDLVISFQLMLCVLDYFIKLSPPMLLKEPYKTAVIPINGSP
RTPRRGQNRSARIAKQLENDTRIIEVLCKEHECNIDEVKNVYFKNFIPFM
NSLGLVTSNGLPEVENLSKRYEEIYLKNKDLDARLFLDHDKTLQTDSIDS
FETQRTPRKSNLDEEVNVIPPHTPVRTVMNTIQQLMMILNSASDQPSENL
ISYFNNCTVNPKESILKRVKDIGYIFKEKFAKAVGQGCVEIGSQRYKLGV
RLYYRVMESMLKSEEERLSIQNFSKLLNDNIFHMSLLACALEVVMATYSR
STSQNLDSGTDLSFPWILNVLNLKAFDFYKVIESFIKAEGNLTREMIKHL
ERCEHRIMESLAWLSDSPLFDLIKQSKDREGPTDHLESACPLNLPLQNNH
TAADMYLSPVRSPKKKGSTTRVNSTANAETQATSAFQTQKPLKSTSLSLF
YKKVYRLAYLRLNTLCERLLSEHPELEHIIWTLFQHTLQNEYELMRDRHL
DQIMMCSMYGICKVKNIDLKFKIIVTAYKDLPHAVQETFKRVLIKEEEYD
SIIVFYNSVFMQRLKTNILQYASTRPPTLSPIPHIPRSPYKFPSSPLRIP
GGNIYISPLKSPYKISEGLPTPTKMTPRSRILVSIGESFGTSEKFQKINQ
MVCNSDRVLKRSAEGSNPPKPLKKLRFDIEGSDEADGSKHLPGESKFQQK
LAEMTSTRTRMQKQKMNDSMDTSNKEEK
Simboli

Supresija ćelijskog ciklusa[uredi | uredi izvor]

pRb ograničava sposobnost ćelije da replicira DNK, sprečavanjem njenog napredovanja iz G1 u S (faza sinteze) .[17] pRb se veže i inhibira vezivajućeg partnera za dimerizaciju proteina (E2F-DP), koji su faktori transkripcije iz porodice E2F koji uvode ćeliju u S-fazu.[18][19][20][21][22][23] Održavajući E2F-DP inaktiviranim, RB1 održava ćeliju u G1 fazi, sprječavajući napredovanje kroz ćelijski ciklus i djelujući kao supresor rasta.[8] Kompleks pRb-E2F/DP također privlači protein zvani histon-deacetilaza (HDAC) u hromatin, smanjujući transkripciju faktora koji promoviraju S fazu, dodatno suzbijajući sintezu DNK.

Aktiviranje i deaktiviranje[uredi | uredi izvor]

Pregled trandukcijskog puta uključennog u apoptozu.

Kad dođe vrijeme za ćeliju da uđe u S fazu, kompleksi ciklin-ovisna kinaza (CDK) i ciklini fosforiliraju pRb, dopuštajući E2F-DP da se disocira od pRb i postane aktivan. Kad je E2F slobodan, aktivira faktore poput ciklina (npr. ciklin E i ciklin A), koji tjeraju ćeliju kroz ćelijski ciklus aktiviranjem kinaza ovisnih o ciklinu, i molekuli koja se naziva proliferirajući ćelijski jedarni antigen ili PCNA , koji ubrzava replikaciju DNK i nje popravak, pomažući pri vezivanju polimeraze za DNK.[24][25]

Deaktivacija[uredi | uredi izvor]

Od 1990-ih godina poznato je da je pRb inaktiviran fosforilacijom. Do tada je prevladavao model da ga je ciklin D-Cdk 4/6 progresivno fosforilirao iz nefosforiliranog u njegovo hiperfosforilirano stanje (14+ fosforilacija). Međutim, nedavno je pokazano da pRb postoji samo u tri stanja: nefosforiliran, monofosforiliran i hiperfosforiliran. Svaki ima jedinstvenu ćelijsku funkciju.[26]

Prije razvoja 2D IEF, samo se hiperfosforilirani pRb razlikovao od svih ostalih oblika, tj. nefosforilirani pRb nalikovao je monofosforiliranom pRb na imunoblotovima. Pošto je pRb bio ili u aktivnom „hipofosforiliranom“ stanju ili u neaktivnom „hiperfosforilisanom“ stanju. Međutim, s 2D IEF-om, sada je poznato da je pRb nefosforiliran u G0 i monofosforiliran u ranim G1 ćelijama, prije hiperfosforilacije, nakon restrikcijske tačke u kasnoj G1 fazi.

Aktivacija[uredi | uredi izvor]

Tokom prijelaza M-u-G1, pRb se zatim progresivno defosforilira, pomoću PP1, vraćajući se u svoje hipofosforilirano stanje koje potiskuje rast.[8][27]

Proteini porodice pRb su komponente DREAM kompleksa, sastavljene od DP, E2F4/5, sličnih RB (p130/p107) i MuvB (Lin9: Lin37: Lin52: RbAbP4: Lin54). Kompleks DREAM sastavljen je u Go/G1 i održava mirovanje, sastavljanjem na promotorima > 800 gena ćelijskog ciklusa i posredovanjem transkripcijske represije. Sklapanje DREAM-a zahtijeva DYRK1A (Ser/Thr kinaza) zavisnu fosforilaciju jedarne komponente MuvB, Lin52 na serinu28. Ovaj mehanizam je ključan za regrutiranje p130/p107 u MuvB jedru, a time i sklopa DREAM.

Interakcije[uredi | uredi izvor]

Poznato je da pRb stupa u interakciju s više od 300 proteina, od kojih su neki navedeni u nastavku:

Također pogledajte[uredi | uredi izvor]

Reference[uredi | uredi izvor]

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