Wikipedia

RB1

(Preusmjereno sa Retinoblastomski protein)

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]

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• vezivanje sa DNK
• 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 vezivanje za proteine
• androgen receptor binding
• vezivanje identičnih proteina
• vezivanje enzima
• 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

5925

19645

Ensembl

ENSG00000139687

ENSMUSG00000022105

UniProt

P06400

P13405

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

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

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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

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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

C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin

Supresija ćelijskog ciklusa

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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

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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

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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

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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

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

Također pogledajte

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Reference

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