PLAC1

Placentnospecifični protein 1 je mali (212 aminokiselinski), sa ćelijske površine lučeći protein koji je kod ljudi kodiran genom PLAC1. Od otkrića 1999., utvrđeno je da PLAC1 ima ulogu u razvoju i održavanju placente, kontroliraju nekoliko gestacijskih poremećaja, uključujući preeklampsiju, razvoj fetusa i veliki broj kancera.

PLAC1
Identifikatori
Aliasi	PLAC1
Vanjski ID-jevi	OMIM: 300296 MGI: 1926287 HomoloGene: 11039 GeneCards: PLAC1
Lokacija gena (čovjek) Hrom. Hromosom X Bend Xq26.3 Početak 134,565,838 bp Kraj 134,764,322 bp
Lokacija gena (miš) Hrom. Hromosom X (miš) Bend X A5|X 29.31 cM Početak 52,158,872 bp Kraj 52,328,988 bp
Obrazac RNK ekspresije Više referentnih podataka o ekspresiji
Ontologija gena Molekularna funkcija • molekularna funkcija Ćelijska komponenta • extracellular region • ćelijska komponenta Biološki proces • multicellular organism development • Placentacija Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	10761	56096
Ensembl	ENSG00000170965	ENSMUSG00000061082
UniProt	Q9HBJ0	Q9JI83
RefSeq (mRNK)	NM_021796 NM_001316887 NM_001316888 NM_001316889	NM_019538 NM_001357802
RefSeq (bjelančevina)	NP_001303816 NP_001303817 NP_001303818 NP_068568	NP_062411 NP_001344731
Lokacija (UCSC)	Chr X: 134.57 – 134.76 Mb	Chr X: 52.16 – 52.33 Mb
PubMed pretraga
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

Genomika

PLAC1 nalazi se na dugom kraku X-hromosoma, na poziciji Xq26.3. Gen se sastoji od šest egzona raspona gotovo 200Kb (GRCh38 / hgs38; X: 134,565,838 - 134,764,322). Čitava kodirajućsa sekvenca plus 3 ’UTR i dio 5’ UTR čine egzon 6, dok egzoni 1 - 5 sadrže različito spojene elemente ostatka 5’UTR, uključujući dva neovisno regulirana promotora. Ova dva promotora, nazvana P1 (distalni) i P2 (proksimalni), nalaze se u egzonima, 1 odnosno 4. Pokazalo se da istovremeno proizvode transkripte, iako transkripcija P1 prevladava u karcinomima, a P2 u placenti .

Filogenetika

Od svog početnog opisa konsenzus je da je PLAC1 visoko konzerviran i da to ima važnu ulogu u uspostavljanju i održavanju placente.

Detaljna studija gena i proteina PLAC1 placente 54 vrste sisara, koji predstavljaju dvanaest krunskih redova potvrđuje visok nivo konzerviranosti pod kontrolom stroge pročišćavajuće selekcije. Dalje, uporedne genomske sekvence dvaju torbara, oposuma (Mondelphis domestica) i valabija ( Macropus eugenii ), monotremata, kljunara (Ornithorhynchus anatinus), dvije ptice, kokoš ( Gallus gallus) i zeba ( Taeniopygia guttata ), te dvije ribe, zebrica (Danio rerio) i gregorac (Gasterosteus aculeatus), u rasponu sintetske regije X-hromosoma iz PHD-prstovog proteina 6 (PHD6) do faktora 9 (F9) pregledana je na bilo koju 'PLAC1-oliku sekvencu. Pokazano je da se PLAC1 pojavio u životinjskom genomu istovremeno s pojavom sisara sa placentom (Placentalia) prije nekih 165 000 000 godina.

Funkcija

Otkriće PLAC1 rezultat je ispitivanja regije oko gena ljudske hipoksantin-ribosiltransferaze 1 (HPRT) s ciljem utvrđivanja da li je tamo kodiran protein specifičan za placentu. Ovo je pitanje pokrenuto jer se vjerovalo da je regija uključena i u patologije placente i fetusa. Nađeno je da se identificirani PLAC1 i njegov mišji ortolog Plac1 eksprimiraju tokom trudnoće. Brzo je utvrđeno da je ekspresija PLAC1 specifična za ćelije trofoblasta i da je presudan element u uspostavljanju i održavanju normalne placente. Ekspresija je dalje lokalizirana na apikalnom području sinciciotrofoblasta, vodećeg, invazivnog dijela embriona u razvoju. Ekspresija PLAC1 prestaje početkom porođaja, a PLAC1 iRNK čiste periferni majčin cirkulacijski sistem ubrzo nakon porođaja.

Prepoznavanje da PLAC1 ima važnu ulogu u prvom uspostavljanju placente, a potom i u njenom održavanju tokom trudnoće dovodi do ideje da PLAC1 može imati ulogu u gestacijskim problemima, od neplodnosti do preranog porođaja. Važan doprinos ovoj ideji je zapažanje da je model nokaut miša Plac1 pokazao placentomegaliju u branama i ograničenje rasta kod mladunaca. Brojni gestacijski problemi povezani su s abnormalnom ekspresijom PLAC1, uključujući unutarmaternično ograničenje rasta (IUGR), prerano rođenje , neuspjeh u implantaciji i preeklampsija. Nekoliko ovih studija nastojalo je razviti PLAC1 testove u dijagnostičke alate sa mješovitim uspjehom.

Kancer

Iako je jasno utvrđeno da je PLAC1 zaista specifičan za posteljicu, gotovo od samog početka bilo je jasno i da je kooptiran kod karcinoma kod ljudi. Prvi dokazi da je PLAC1 kooptiran za rak objavljeni su 2006. Od tada, ekspresija PLAC1 dokazana je u više od desetak ljudskih karcinoma i u najmanje stotinu ćelijskih linija tih karcinoma. Među karcinomima kod kojih je izražena ekspresija PLAC1 su karcinomi želuca karcinomi debelog crijeva/debelog crijeva., karcinomi jetre, karcinomi gušterače, karcinomi pluća i rak dojke. U gotovo svim slučajevima, ekspresija PLAC1 povezana je sa lošim kliničkim ishodima. Nigdje ovo nije tako kao kod karcinoma muškog i ženskog reproduktivnog trakta. Odnosno, rak prostate rak maternice , rak jajnika i rak grlića maternice [55] pokazali su pozitivnu korelaciju između ekspresije PLAC1 i prognoze.

U 2005., pokazalo se da je ekspresija PLAC1 u diferenciranju fibroblasta regulirana njihovim faktorom rasta 7 (FGF7). Otada se pokazalo da je ovaj regulatorni odnos presudan za proliferaciju ćelija karcinoma posredovanu serin/ treonin kinazom . PLAC1 formira kompleks ćelijske površine sa FGF7 i receptorom FGFR2IIIb, koji zatim aktivira kaskadu koja dovodi do fosforilacije Akt-a. Ekspresija PLAC1 zauzvrat je djelomično određena supresijom tumora. Ekspresija PLAC1 potiskuje p53 divljeg tipa, ali se povećava u prisustvu mutiranog ili odsutnog.

Imunoterapija

PLAC1 je klasificiran kao „antigen karcinoma testisa”, jer se preferencijalno izražava u trofoblastima i tumorima. Pored rezultata koji povezuju ekspresiju PLAC1 s rizikom od različitih karcinoma kao i s prognozom, sposobnost PLAC1 da izazove imunski odgovor sugerira da bi se njegova specifičnost mogla terapijski iskoristiti. Jedna grupa posebno prednjači u potencijalu. Korištenjem konjugata anti-PLAC1/ lijek pokazali su da imunoterapija zasnovana na PLAC1 vrlo obećava . Nejadmoghaddam MR, Zarnani AH, Ghahremanzadeh R, Ghods R, Mahmoudian J, Yousefi M, Nazari M, Ghahremani MH, Abolhasani M, Anissian A, Mahmoudi M, Dinarvand R. 2017 Placenta-specific1 (PLAC1) is a potential target for antibody-drug conjugate-based prostate cancer immunotherapy. Sci Rep. Oct 17;7(1):13373. doi: 10.1038/s41598-017-13682-9. PubMed

Dopunska literatura

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