PAX3

PAX3
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	3CMY
Identifikatori
Aliasi	PAX3
Vanjski ID-jevi	OMIM: 606597 MGI: 97487 HomoloGene: 22494 GeneCards: PAX3
Lokacija gena (čovjek)
Hrom.	Hromosom 2 (čovjek)
Kraj	222,298,998 bp
Lokacija gena (miš)
Hrom.	Hromosom 1 (miš)
Kraj	78,173,771 bp
Obrazac RNK ekspresije
	; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• HMG box domain binding; • vezivanje sa DNK; • GO:0001948, GO:0016582 vezivanje za proteine; • sequence-specific DNA binding; • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity; • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific;
Ćelijska komponenta	• jedro; • nukleoplazma;
Biološki proces	• animal organ morphogenesis; • GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated; • multicellular organism development; • muscle organ development; • GO:0009373 regulation of transcription, DNA-templated; • transcription by RNA polymerase II; • sluh; • transcription, DNA-templated; • nervous system development; • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II; • GO:0097285 apoptoza;
	Izvori:Amigo / QuickGO
Ortolozi
	5077
	18505
	ENSG00000135903
	ENSMUSG00000004872
	P23760
	P24610
NM_000438; NM_001127366; NM_013942; NM_181457; NM_181458;
	NM_181459; NM_181460; NM_181461
	NM_001159520; NM_008781
NP_000429; NP_001120838; NP_039230; NP_852122; NP_852123;
	NP_852124; NP_852125; NP_852126; NP_852122.1
	NP_001152992; NP_032807
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

PAX3 (gen 3 uparene kuitije) jest gen koji se kod ljudi balazi na hromosomu 2. Kodira člana uparene kutije ili porodice PAX transkripcijskih faktora.^[5] Porodica PAX sastoji se od devet ljudskih (PAX1-PAX9) i devet mišjih (Pax1-Pax9) članova raspoređenih u četiri potporodice. Ljudski PAX3 i mišji Pax3 prisutni su u podporodici zajedno sa visoko homolognim ljudskim PAX7 i mišjim Pax7 genima. Ljudski PAX3 gen nalazi se u hromozomskoj regiji 2q36.1 i sadrži 10 egzona unutar 100 kb regiona.

Prerada transkripta

Alternativna prerafa i obrada generira višestruke PAX3 izoforme koje su otkrivene na nivou iRNK.^[6] PAX3e je najduža izoforma i sastoji se od 10 egzona koji kodiraju protein od 505 aminokiselina. Kod drugih vrsta sisara, uključujući miša, najduže iRNK odgovaraju izoformama PAX3c i PAX3d čovjeka, koje se sastoje od prvih osam ili devet egzona gena PAX3. Kraće PAX3 izoforme uključuju iRNK koje preskaču egzon 8 (PAX3g i PAX3h) i iRNK koje sadrže četiri ili pet egzona (PAX3a i PAX3b). U ograničenim studijama koje upoređuju ekspresiju izoforme, PAX3d je izražen na najvišim nivoima. ]Sa funkcionalnog stanovišta, PAX3c, PAX3d i PAX3h stimulišu aktivnosti kao što je rast ćelija, dok PAX3e i PAX3g inhibiraju ove aktivnosti, a PAX3a i PAX3b ne pokazuju nikakvu aktivnost ili inhibiraju ove krajnje tačke.

Uobičajea [[alternativna prerada koja utiče na PAX3 iRNK uključuje sekvencu CAG na 5' kraju egzona 3.^[7] Ovaprerada ili uključuje ili isključuje ove tri baze, što rezultira prisustvom ili odsustvom glutamin]skih ostataka u motivu uparene kutije. Ograničene studije sekvenciranja ljudskih cDNK pune dužine identificirale su ovaj događaj prerade kao varijantu izoforme PAX3d, a ova prerašđena izoforma je odvojeno nazvana PAX3i izoforma. Q+ i Q- izoforme PAX3 općenitoo se koeksprimiraju u ćelijama. Na funkcionalnom nivou, Q+ izoforma pokazuje slično ili manje vezivanje DNK i aktivaciju transkripcije od Q- izoforme.

Amiokiselininska sekvenca

Dužina polipeptidnog lanca je 479 aminokiselina, a molekulska težina 52.968 Da.^[8]

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

10	20	30	40	50
MTTLAGAVPR	MMRPGPGQNY	PRSGFPLEVS	TPLGQGRVNQ	LGGVFINGRP
LPNHIRHKIV	EMAHHGIRPC	VISRQLRVSH	GCVSKILCRY	QETGSIRPGA
IGGSKPKQVT	TPDVEKKIEE	YKRENPGMFS	WEIRDKLLKD	AVCDRNTVPS
VSSISRILRS	KFGKGEEEEA	DLERKEAEES	EKKAKHSIDG	ILSERASAPQ
SDEGSDIDSE	PDLPLKRKQR	RSRTTFTAEQ	LEELERAFER	THYPDIYTRE
ELAQRAKLTE	ARVQVWFSNR	RARWRKQAGA	NQLMAFNHLI	PGGFPPTAMP
TLPTYQLSET	SYQPTSIPQA	VSDPSSTVHR	PQPLPPSTVH	QSTIPSNPDS
SSAYCLPSTR	HGFSSYTDSF	VPPSGPSNPM	NPTIGNGLSP	QVMGLLTNHG
GVPHQPQTDY	ALSPLTGGLE	PTTTVSASCS	QRLDHMKSLD	SLPTSQSYCP
PTYSTTGYSM	DPVTGYQYGQ	YGQSKPWTF

Struktura i funkcija proteina

'Struktura *PAX3* gena, iRNK i proteina: Egzoni u DNK i iRNK dijagramima su numerisani, a horizontalna strelica na DNK dijagramu pokazuje promotor i pravac transkripcije. Startni i stop kodoni prikazani su na dijagramu iRNK vertikalnim strelicama. Konzervirane regije su označene otvorenim okvirima u dijagramu proteina, a funkcionalni domeni su označeni debelim horizontalnim linijama iznad dijagrama proteina. Reprezentativne veličine su prikazane tankim horizontalnim segmentima u dijagramima DNK, iRNK i proteina. Skraćenice: PB = upareni bokutijski domen; HD = homeodomen; PST = regija bogata prolinom, serinom i treoninom; DBD= DNK vezujući domen; TAD = domen aktivacije transkripcije.

PAX3 kodira faktor transkripcije sa N-terminalnim DNK vezujućim domenom- koji se sastoji od uparene kutije (PD) kodiranog egzonima 2, 3 i 4, i oktapeptida i kompletnog homeodomena (HD) kodiranpg egzonima 5 i 6.^[9] Pored toga, PAX3 protein ima domen transkripcijske aktivacije C-terminala kodiran egzonima 7 i 8. Visoko konzervirani PD sastoji se od regiona od 128 aminokiselina koji se vezuje za DNK sekvence povezane sa TCACGC/G motivom.^[10] HD motiv se obično sastoji od 60 aminokiselina i veže se za sekvence koje sadrže motiv jezgra TAAT.^[11] The combination of these two DNA binding domains enable the PAX3 protein to recognize longer sequences containing PD and HD binding sites.^[12] U C-terminalu PAX3, nalazi se regija bogata prolinom, serinom i treoninom (PST) koja mjeri 78 aminokiselina i stimulira transkripcijsku aktivnost..^[13] Postoje i domeni represije transkripcije u HD i N-terminalnom regionu (uključujući prvu polovinu PD), koji potiskuju domen C-terminalne transkripcione aktivacije.^[14]

PAX3 funkcionira kao aktivator transkripcije za većinu ciljnih gena, ali također može potisnuti manji podskup ciljnih gena.^[15] Ove promene ekspresije se vrše vezivanjem PAX3 za specifična mesta prepoznavanja, koja se nalaze na različitim genomskim lokacijama.^[16]

Tabeta 1: Reprezentativni PAX3 transkripcijski ciljni geni

Proteinska kategoroja	Naziv	Fenotipska aktivnost
Molekula ćelijske adhezije	NRCAM	Međućelijka adhezija
Hemokinski receptor	CXCR4	Pokretljivost
Receptor tirozin-kinaza	FGFR4	Proliferacija, diferencijacija, migracija
	MET	Proliferacija, migracija, preživljavanje
	RET	Prolifercija, migracija, diferecijacija
Transkripcijsi faktor	MITF	Diferencijacija, proliferacija, preživljavanje
	MYF5	Diferencijacija
	MYOD1	Diferencijacija

Napomene

Greška: Imena pokazatelja stanja stranice ne smiju biti prazna.

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000135903 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000004872 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Stuart ET, Kioussi C, Gruss P (1994). "Mammalian Pax genes". review. Annual Review of Genetics. 28: 219–36. doi:10.1146/annurev.ge.28.120194.001251. PMID 7893124.
^ Wang Q, Fang WH, Krupinski J, Kumar S, Slevin M, Kumar P (decembar 2008). "Pax genes in embryogenesis and oncogenesis". review. Journal of Cellular and Molecular Medicine. 12 (6A): 2281–94. doi:10.1111/j.1582-4934.2008.00427.x. PMC 4514106. PMID 18627422.
^ Vogan KJ, Underhill DA, Gros P (decembar 1996). "An alternative splicing event in the Pax-3 paired domain identifies the linker region as a key determinant of paired domain DNA-binding activity". primary. Molecular and Cellular Biology. 16 (12): 6677–86. doi:10.1128/mcb.16.12.6677. PMC 231670. PMID 8943322.
^ "UniProt, P23760" (jezik: engleski). Pristupljeno 18. 11. 2021.
^ Baldwin CT, Hoth CF, Macina RA, Milunsky A (august 1995). "Mutations in PAX3 that cause Waardenburg syndrome type I: ten new mutations and review of the literature". review. American Journal of Medical Genetics. 58 (2): 115–22. doi:10.1002/ajmg.1320580205. PMID 8533800.
^ Jun S, Desplan C (septembar 1996). "Cooperative interactions between paired domain and homeodomain". primary. Development. 122 (9): 2639–50. doi:10.1242/dev.122.9.2639. PMID 8787739.
^ Wilson D, Sheng G, Lecuit T, Dostatni N, Desplan C (novembar 1993). "Cooperative dimerization of paired class homeo domains on DNA". primary. Genes & Development. 7 (11): 2120–34. doi:10.1101/gad.7.11.2120. PMID 7901121.
^ Phelan SA, Loeken MR (juli 1998). "Identification of a new binding motif for the paired domain of Pax-3 and unusual characteristics of spacing of bipartite recognition elements on binding and transcription activation". primary. The Journal of Biological Chemistry. 273 (30): 19153–9. doi:10.1074/jbc.273.30.19153. PMID 9668101.
^ Bennicelli JL, Fredericks WJ, Wilson RB, Rauscher FJ, Barr FG (juli 1995). "Wild type PAX3 protein and the PAX3-FKHR fusion protein of alveolar rhabdomyosarcoma contain potent, structurally distinct transcriptional activation domains". primary. Oncogene. 11 (1): 119–30. PMID 7624119.
^ Bennicelli JL, Edwards RH, Barr FG (maj 1996). "Mechanism for transcriptional gain of function resulting from chromosomal translocation in alveolar rhabdomyosarcoma". primary. Proceedings of the National Academy of Sciences of the United States of America. 93 (11): 5455–9. doi:10.1073/pnas.93.11.5455. PMC 39267. PMID 8643596.
^ Mayanil CS, George D, Freilich L, Miljan EJ, Mania-Farnell B, McLone DG, Bremer EG (decembar 2001). "Microarray analysis detects novel Pax3 downstream target genes". primary. The Journal of Biological Chemistry. 276 (52): 49299–309. doi:10.1074/jbc.M107933200. PMID 11590174.
^ Soleimani VD, Punch VG, Kawabe Y, Jones AE, Palidwor GA, Porter CJ, Cross JW, Carvajal JJ, Kockx CE, van IJcken WF, Perkins TJ, Rigby PW, Grosveld F, Rudnicki MA (juni 2012). "Transcriptional dominance of Pax7 in adult myogenesis is due to high-affinity recognition of homeodomain motifs". primary. Developmental Cell. 22 (6): 1208–20. doi:10.1016/j.devcel.2012.03.014. PMC 3376216. PMID 22609161.

Dopunska literatura

Wachtel M, Schäfer BW (2017). "PAX3-FOXO1: Zooming in on an "undruggable" target". review. Seminars in Cancer Biology. 50: 115–123. doi:10.1016/j.semcancer.2017.11.006. PMID 29146205.
Kubo T, Shimose S, Fujimori J, Furuta T, Ochi M (2015). "Prognostic value of PAX3/7-FOXO1 fusion status in alveolar rhabdomyosarcoma: Systematic review and meta-analysis". review. Critical Reviews in Oncology/Hematology. 96 (1): 46–53. doi:10.1016/j.critrevonc.2015.04.012. PMID 26008753.
Buckingham M, Relaix F (2015). "PAX3 and PAX7 as upstream regulators of myogenesis". review. Seminars in Cell & Developmental Biology. 44: 115–25. doi:10.1016/j.semcdb.2015.09.017. PMID 26424495.
Eccles MR, He S, Ahn A, Slobbe LJ, Jeffs AR, Yoon HS, Baguley BC (2013). "MITF and PAX3 Play Distinct Roles in Melanoma Cell Migration; Outline of a "Genetic Switch" Theory Involving MITF and PAX3 in Proliferative and Invasive Phenotypes of Melanoma". review. Frontiers in Oncology. 3: 229. doi:10.3389/fonc.2013.00229. PMC 3769631. PMID 24062982.
Olanich ME, Barr FG (2013). "A call to ARMS: targeting the PAX3-FOXO1 gene in alveolar rhabdomyosarcoma". review. Expert Opinion on Therapeutic Targets. 17 (5): 607–23. doi:10.1517/14728222.2013.772136. PMC 6699745. PMID 23432728.
Medic S, Ziman M (2009). "PAX3 across the spectrum: from melanoblast to melanoma". review. Critical Reviews in Biochemistry and Molecular Biology. 44 (2–3): 85–97. doi:10.1080/10409230902755056. PMID 19401874. S2CID 20634846.
Kubic JD, Young KP, Plummer RS, Ludvik AE, Lang D (2008). "Pigmentation PAX-ways: the role of Pax3 in melanogenesis, melanocyte stem cell maintenance, and disease". review. Pigment Cell & Melanoma Research. 21 (6): 627–45. doi:10.1111/j.1755-148X.2008.00514.x. PMC 2979299. PMID 18983540.

Vanjski linkovi

PAX3 protein, human na US National Library of Medicine Medical Subject Headings (MeSH)
P23760

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000135903 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000004872 - Ensembl, maj 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[5] Stuart ET, Kioussi C, Gruss P (1994). "Mammalian Pax genes". review. Annual Review of Genetics. 28: 219–36. doi:10.1146/annurev.ge.28.120194.001251. PMID 7893124.

[6] Wang Q, Fang WH, Krupinski J, Kumar S, Slevin M, Kumar P (decembar 2008). "Pax genes in embryogenesis and oncogenesis". review. Journal of Cellular and Molecular Medicine. 12 (6A): 2281–94. doi:10.1111/j.1582-4934.2008.00427.x. PMC 4514106. PMID 18627422.

[7] Vogan KJ, Underhill DA, Gros P (decembar 1996). "An alternative splicing event in the Pax-3 paired domain identifies the linker region as a key determinant of paired domain DNA-binding activity". primary. Molecular and Cellular Biology. 16 (12): 6677–86. doi:10.1128/mcb.16.12.6677. PMC 231670. PMID 8943322.

[UniProt-8] "UniProt, P23760" (jezik: engleski). Pristupljeno 18. 11. 2021.

[9] Baldwin CT, Hoth CF, Macina RA, Milunsky A (august 1995). "Mutations in PAX3 that cause Waardenburg syndrome type I: ten new mutations and review of the literature". review. American Journal of Medical Genetics. 58 (2): 115–22. doi:10.1002/ajmg.1320580205. PMID 8533800.

[10] Jun S, Desplan C (septembar 1996). "Cooperative interactions between paired domain and homeodomain". primary. Development. 122 (9): 2639–50. doi:10.1242/dev.122.9.2639. PMID 8787739.

[11] Wilson D, Sheng G, Lecuit T, Dostatni N, Desplan C (novembar 1993). "Cooperative dimerization of paired class homeo domains on DNA". primary. Genes & Development. 7 (11): 2120–34. doi:10.1101/gad.7.11.2120. PMID 7901121.

[12] Phelan SA, Loeken MR (juli 1998). "Identification of a new binding motif for the paired domain of Pax-3 and unusual characteristics of spacing of bipartite recognition elements on binding and transcription activation". primary. The Journal of Biological Chemistry. 273 (30): 19153–9. doi:10.1074/jbc.273.30.19153. PMID 9668101.

[13] Bennicelli JL, Fredericks WJ, Wilson RB, Rauscher FJ, Barr FG (juli 1995). "Wild type PAX3 protein and the PAX3-FKHR fusion protein of alveolar rhabdomyosarcoma contain potent, structurally distinct transcriptional activation domains". primary. Oncogene. 11 (1): 119–30. PMID 7624119.

[Bennicelli_1996-14] Bennicelli JL, Edwards RH, Barr FG (maj 1996). "Mechanism for transcriptional gain of function resulting from chromosomal translocation in alveolar rhabdomyosarcoma". primary. Proceedings of the National Academy of Sciences of the United States of America. 93 (11): 5455–9. doi:10.1073/pnas.93.11.5455. PMC 39267. PMID 8643596.

[15] Mayanil CS, George D, Freilich L, Miljan EJ, Mania-Farnell B, McLone DG, Bremer EG (decembar 2001). "Microarray analysis detects novel Pax3 downstream target genes". primary. The Journal of Biological Chemistry. 276 (52): 49299–309. doi:10.1074/jbc.M107933200. PMID 11590174.

[16] Soleimani VD, Punch VG, Kawabe Y, Jones AE, Palidwor GA, Porter CJ, Cross JW, Carvajal JJ, Kockx CE, van IJcken WF, Perkins TJ, Rigby PW, Grosveld F, Rudnicki MA (juni 2012). "Transcriptional dominance of Pax7 in adult myogenesis is due to high-affinity recognition of homeodomain motifs". primary. Developmental Cell. 22 (6): 1208–20. doi:10.1016/j.devcel.2012.03.014. PMC 3376216. PMID 22609161.

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