RUNX1

Runt-srodni transkripcijski faktor 1 (RUNX1), znan i kao protein 1 akutne mijeloidne leukemije (AML1) ili podjedinica alfa-2 jezgarno vezanog faktora (CBFA2) jest protein koji je kod ljudi kodiran genom RUNX1 sa hromosoma 21.^[5][6]

RUNX1
Dostupne strukture PDB Pretraga ortologa: PDBe RCSB Spisak PDB ID kodova 1CMO, 1CO1, 1E50, 1H9D, 1LJM
Identifikatori
Aliasi	RUNX1
Vanjski ID-jevi	OMIM: 151385 MGI: 99852 HomoloGene: 1331 GeneCards: RUNX1
Lokacija gena (čovjek) Hrom. Hromosom 21 (čovjek)[1] Bend 21q22.12 Početak 34,787,801 bp[1] Kraj 36,004,667 bp[1]
Lokacija gena (miš) Hrom. Hromosom 16 (miš)[2] Bend 16 C4|16 53.7 cM Početak 92,398,354 bp[2] Kraj 92,623,037 bp[2]
Obrazac RNK ekspresije Više referentnih podataka o ekspresiji
Ontologija gena Molekularna funkcija • vezivanje sa DNK • calcium ion binding • RNA polymerase II transcription regulatory region sequence-specific DNA binding • protein homodimerization activity • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific • transcription factor binding • GO:0001948, GO:0016582 vezivanje za proteine • protein heterodimerization activity • ATP binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding Ćelijska komponenta • intracellular membrane-bounded organelle • jedro • citosol • nukleoplazma • core-binding factor complex Biološki proces • peripheral nervous system neuron development • myeloid cell differentiation • GO:0009373 regulation of transcription, DNA-templated • chondrocyte differentiation • ossification • negative regulation of granulocyte differentiation • hematopoietic stem cell proliferation • transcription, DNA-templated • positive regulation of angiogenesis • GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated • positive regulation of interleukin-2 production • positive regulation of granulocyte differentiation • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II • transcription by RNA polymerase II • regulation of cytokine-mediated signaling pathway • regulation of Wnt signaling pathway • regulation of intracellular estrogen receptor signaling pathway • regulation of regulatory T cell differentiation • regulation of keratinocyte differentiation • regulation of myeloid cell differentiation • regulation of megakaryocyte differentiation • regulation of B cell receptor signaling pathway • regulation of hematopoietic stem cell differentiation • regulation of bicellular tight junction assembly • Hematopoeza • GO:1901227 negative regulation of transcription by RNA polymerase II • negative regulation of CD4-positive, alpha-beta T cell differentiation • positive regulation of CD8-positive, alpha-beta T cell differentiation • negative regulation of gene expression • neuron differentiation Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	861	12394
Ensembl	ENSG00000159216	ENSMUSG00000022952
UniProt	Q01196	Q03347
RefSeq (mRNK)	NM_001001890 NM_001122607 NM_001754	NM_001111021 NM_001111022 NM_001111023 NM_009821
RefSeq (bjelančevina)	NP_001001890 NP_001116079 NP_001745	n/a
Lokacija (UCSC)	Chr 21: 34.79 – 36 Mb	Chr 16: 92.4 – 92.62 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 453 aminokiseline, a molekulska težina 48.737 Da.^[6]

• 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
MRIPVDASTS		RRFTPPSTAL		SPGKMSEALP		LGAPDAGAAL		AGKLRSGDRS
MVEVLADHPG		ELVRTDSPNF		LCSVLPTHWR		CNKTLPIAFK		VVALGDVPDG
TLVTVMAGND		ENYSAELRNA		TAAMKNQVAR		FNDLRFVGRS		GRGKSFTLTI
TVFTNPPQVA		TYHRAIKITV		DGPREPRRHR		QKLDDQTKPG		SLSFSERLSE
LEQLRRTAMR		VSPHHPAPTP		NPRASLNHST		AFNPQPQSQM		QDTRQIQPSP
PWSYDQSYQY		LGSIASPSVH		PATPISPGRA		SGMTTLSAEL		SSRLSTAPDL
TAFSDPRQFP		ALPSISDPRM		HYPGAFTYSP		TPVTSGIGIG		MSAMGSATRY
HTYLPPPYPG		SSQAQGGPFQ		ASSPSYHLYY		GASAGSYQFS		MVGGERSPPR
ILPPCTNAST		GSALLNPSLP		NQSDVVEAEG		SHSNSPTNMA		PSARLEEAVW
RPY

Gen i protein

Kod ljudi, gen RUNX1 je dug 260 kilobaza (kb) i nalazi se na hromosomu 21 (21q22.12). Gen se može transkribirati preko dva alternativna promotora, promotor 1 (distalni) ili promotor 2 (proksimalni). Kao rezultat, različite izoforme runx1 mogu biti sintetizovane, što je olakšano alternativnom preradom. RUNX1 protein pune dužine kodiran je sa 12 egzona. Među egzonima su dva definirana domena, domen homologije runt (RHD) ili runt domen (egzoni 2, 3 i 4) i domen transaktivacije (TAD) (egzon 6). Ovi domeni su neophodni da RUNX1 posreduje u vezivanju DNK i interakciji protein-protein. Transkripciju RUNX1 reguliraju dva pojačivača (regulatorni element 1 i regulatorni element 2), a ovi tkivno specifični pojačivači omogućavaju vezivanje limfoidnih ili eritroidnih regulatornih proteina; stoga je genska aktivnost RUNX1 visoko aktivana u hematopoetskom sistemu.

Protein RUNX1 sastoji se od 453 aminokiseline. Kao faktor transkripcije (TF), njegova sposobnost vezivanja za DNK je kodirana runt domenom (ostaci 50 – 177), koji je homologan porodici p53. Runt domen RUNX1 se veže za osnovnu konsenzusnu sekvencu TGTGGNNN (gde NNN može predstavljati ili TTT ili TCA).^[7] Prepoznavanje DNK postiže se petljama 12-lančanog β-barela i C-terminalnog "repa" (ostaci 170 – 177), koji se stežu oko kičme šećernog fosfata i uklapaju se u glavne i male spirale DNK. Specifičnost se postiže direktnim ili vodenim kontaktima sa bazama. RUNX1 može da veže DNK kao monomer, ali njegov afinitet vezivanja za DNK povećava se 10 puta ako se heterodimerizuje sa faktorom vezivanja jezgra β (CBFβ), također preko runt domena. U stvari, porodica RUNX naziva se često α-podjedinicama, zajedno sa vezivanjem zajedničke β-podjedinice CBFβ, RUNX se može ponašati kao heterodimerni faktori transkripcije koji se zajednički nazivaju jezgarno vezujući faktori (CBFs).

Utvrđeno je da je konsenzusno vezujuće mjesto za CBF sekvenca od 7 bp PyGPyGGTPy. Py označava pirimidin koji može biti ili citozin ili timin.^[8]

Funkcija

RUNX1 je transkripcijski faktor koji reguliše diferencijaciju hematopoetskih matičnih ćelija u zrele krvne ćelije.^[9] Osim toga, ima važnu ulogu u razvoju neurona koji prenose osjećaj boli.^[10] Pripada porodici gena vezanih za transkripcijski faktor (RUNX) koji se takođe nazivaju faktori jezgarnog vezivanja-α (CBFα). RUNX proteini formiraju heterodimerni proteinski kompleks sa CBFβ koji omogućava povećano vezivanje DNK i stabilnost kompleksa.

Klinički značaj

Hromosomske translokacije koje uključuju gen RUNX1 povezane su s nekoliko tipova leukemija uključujući akutnu mijeloblastnu leukemiju sa sazrijevanjem]] (M2 AML).^[11] Mutacije u RUNX1 upletene su u slučajeve raka dojke.^[12]

Interakcije

Pokazano je da RUNX1 reaguje sa:

• C-Fos,^[13][14]
• C-jun,^[13][14]
• SUV39H1^[15]
• TLE1,^[16]
• VDR.^[17] i
• Stat3^[17]

Također pogledajte

• RUNX2
• RUNX3

Reference

1. GRCh38: Ensembl release 89: ENSG00000159216 - Ensembl, maj 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000022952 - 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. "Entrez Gene: RUNX1 runt-related transcription factor 1 (acute myeloid leukemia 1; aml1 oncogene)".
6. Avramopoulos D, Cox T, Blaschak JE, Chakravarti A, Antonarakis SE (October 1992). "Linkage mapping of the AML1 gene on human chromosome 21 using a DNA polymorphism in the 3' untranslated region". Genomics. 14 (2): 506–7. doi:10.1016/S0888-7543(05)80253-8. PMID 1427868.
7. Bowers SR, Calero-Nieto FJ, Valeaux S, Fernandez-Fuentes N, Cockerill PN (October 2010). "Runx1 binds as a dimeric complex to overlapping Runx1 sites within a palindromic element in the human GM-CSF enhancer". Nucleic Acids Research. 38 (18): 6124–34. doi:10.1093/nar/gkq356. PMC 2952845. PMID 20483917.
8. Melnikova IN, Crute BE, Wang S, Speck NA (April 1993). "Sequence specificity of the core-binding factor". Journal of Virology. 67 (4): 2408–11. doi:10.1128/JVI.67.4.2408-2411.1993. PMC 240414. PMID 8445737.
9. Okuda T, Nishimura M, Nakao M, Fujita Y (October 2001). "RUNX1/AML1: a central player in hematopoiesis". International Journal of Hematology. 74 (3): 252–7. doi:10.1007/bf02982057. PMID 11721959. S2CID 5918511.
10. Chen CL, Broom DC, Liu Y, de Nooij JC, Li Z, Cen C, Samad OA, Jessell TM, Woolf CJ, Ma Q (February 2006). "Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain". Neuron. 49 (3): 365–77. doi:10.1016/j.neuron.2005.10.036. PMID 16446141. S2CID 16070223.
11. Asou N (February 2003). "The role of a Runt domain transcription factor AML1/RUNX1 in leukemogenesis and its clinical implications". Critical Reviews in Oncology/Hematology. 45 (2): 129–50. doi:10.1016/S1040-8428(02)00003-3. PMID 12604126.
12. Koboldt DC (October 2012). "Comprehensive molecular portraits of human breast tumours". Nature. Nature Publishing Group. 490 (7418): 61–70. Bibcode:2012Natur.490...61T. doi:10.1038/nature11412. PMC 3465532. PMID 23000897.
13. Hess J, Porte D, Munz C, Angel P (June 2001). "AP-1 and Cbfa/runt physically interact and regulate parathyroid hormone-dependent MMP13 expression in osteoblasts through a new osteoblast-specific element 2/AP-1 composite element". The Journal of Biological Chemistry. 276 (23): 20029–38. doi:10.1074/jbc.M010601200. PMID 11274169.
14. D'Alonzo RC, Selvamurugan N, Karsenty G, Partridge NC (January 2002). "Physical interaction of the activator protein-1 factors c-Fos and c-Jun with Cbfa1 for collagenase-3 promoter activation". The Journal of Biological Chemistry. 277 (1): 816–22. doi:10.1074/jbc.M107082200. PMID 11641401.
15. Chakraborty S, Sinha KK, Senyuk V, Nucifora G (August 2003). "SUV39H1 interacts with AML1 and abrogates AML1 transactivity. AML1 is methylated in vivo". Oncogene. 22 (34): 5229–37. doi:10.1038/sj.onc.1206600. PMID 12917624.
16. Levanon D, Goldstein RE, Bernstein Y, Tang H, Goldenberg D, Stifani S, Paroush Z, Groner Y (September 1998). "Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors". Proceedings of the National Academy of Sciences of the United States of America. 95 (20): 11590–5. Bibcode:1998PNAS...9511590L. doi:10.1073/pnas.95.20.11590. PMC 21685. PMID 9751710.
17. Puccetti E, Obradovic D, Beissert T, Bianchini A, Washburn B, Chiaradonna F, Boehrer S, Hoelzer D, Ottmann OG, Pelicci PG, Nervi C, Ruthardt M (December 2002). "AML-associated translocation products block vitamin D(3)-induced differentiation by sequestering the vitamin D(3) receptor". Cancer Research. 62 (23): 7050–8. PMID 12460926.

Dopunska literatura

• Nucifora G, Rowley JD (July 1995). "AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia". Blood. 86 (1): 1–14. doi:10.1182/blood.V86.1.1.bloodjournal8611. PMID 7795214.
• Perry C, Eldor A, Soreq H (March 2002). "Runx1/AML1 in leukemia: disrupted association with diverse protein partners". Leukemia Research. 26 (3): 221–8. doi:10.1016/S0145-2126(01)00128-X. PMID 11792409.
• Imai O, Kurokawa M, Izutsu K, Hangaishi A, Maki K, Ogawa S, Chiba S, Mitani K, Hirai H (March 2002). "Mutational analyses of the AML1 gene in patients with myelodysplastic syndrome". Leukemia & Lymphoma. 43 (3): 617–21. doi:10.1080/10428190290012155. PMID 12002768. S2CID 45854670.
• Hart SM, Foroni L (December 2002). "Core binding factor genes and human leukemia". Haematologica. 87 (12): 1307–23. PMID 12495904.
• Michaud J, Scott HS, Escher R (2003). "AML1 interconnected pathways of leukemogenesis". Cancer Investigation. 21 (1): 105–36. doi:10.1081/CNV-120018821. PMID 12643014. S2CID 19586636.
• Ganly P, Walker LC, Morris CM (January 2004). "Familial mutations of the transcription factor RUNX1 (AML1, CBFA2) predispose to acute myeloid leukemia". Leukemia & Lymphoma. 45 (1): 1–10. doi:10.1080/1042819031000139611. PMID 15061191. S2CID 10770839.
• Yamada R, Tokuhiro S, Chang X, Yamamoto K (September 2004). "SLC22A4 and RUNX1: identification of RA susceptible genes". Journal of Molecular Medicine. 82 (9): 558–64. doi:10.1007/s00109-004-0547-y. PMID 15184985. S2CID 9156168.
• Harada H, Harada Y, Kimura A (September 2006). "Implications of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome (MDS): future molecular therapeutic directions for MDS". Current Cancer Drug Targets. 6 (6): 553–65. doi:10.2174/156800906778194595. PMID 17017876.

Vanjsi linkovi

• RUNX1 protein, human na US National Library of Medicine Medical Subject Headings (MeSH)
• Q01196
• Q03347