IRX1

Iroquois homeobox 1
Identifiers
Symbols IRX1 ; IRX-5; IRXA1
External IDs OMIM: 606197 MGI: 1197515 HomoloGene: 19065 GeneCards: IRX1 Gene
Orthologs
Species Human Mouse
Entrez 79192 16371
Ensembl ENSG00000170549 ENSMUSG00000060969
UniProt P78414 P81068
RefSeq (mRNA) NM_024337 NM_010573
RefSeq (protein) NP_077313 NP_034703
Location (UCSC) Chr 5:
3.6 – 3.6 Mb		 Chr 13:
71.96 – 71.96 Mb
PubMed search

Iroquois-class homeodomain protein IRX-1, also known as Iroquois homeobox protein 1, is a protein that in humans is encoded by the IRX1 gene.[1][2] All members of the Iroquois (IRO) family of proteins share two highly conserved features, encoding both a homeodomain and a characteristic IRO sequence motif.[3] Members of this family are known to play numerous roles in early embryo patterning.[1] IRX1 has also been shown to act as a tumor suppressor gene in several forms of cancer.[4][5][6][7]

Role in development

IRX1 is a member of the Iroquois homeobox gene family. Members of this family play multiple roles during pattern formation in embryos of numerous vertebrate and invertebrate species.[1][8] IRO genes are thought to function early in development to define large territories, and again later in development for further patterning specification.[3] Experimental data suggest roles for IRX1 in vertebrates may include development and patterning of lungs, limbs, heart, eyes, and nervous system.[9][10][11][12][13][14]

Gene

Overview

IRX1 is located on the forward DNA strand (see Sense (molecular biology)) of chromosome 5, from position 3596054 - 3601403 at the 5p15.3 location.[1] The human gene product is a 1858 base pair mRNA with 4 predicted exons in humans.[15] Promoter analysis was performed using El Dorado through the Genomatix software page.[16] The predicted promoter region spans 1040 base pairs from position 3595468 through 3595468 on the forward strand of chromosome 5.

Gene neighborhood

IRX1 is relatively isolated, with no other protein coding genes found from position 3177835 – 5070004.[1]

Expression

Microarray and RNA seq data suggest that IRX1 is ubiquitously expressed at low levels in adult tissues, with the highest relative levels of expression occurring in the heart, adipose, kidney, and breast tissues.[17][18] Moderate to high levels are also indicated in the lung, prostate and stomach.[18][19] Promoter analysis with the El Dorado program from Genomatix predicted that IRX1 expression is regulated by factors that include E2F cell cycle regulators, NRF1, and ZF5,[20] and brachyury.[16] Expression data from human, mouse, and developing mouse brains are available though the Allen Brain Atlas.[21]

Protein

Properties & characteristics

The mature IRX1 protein has 480 amino acid residues, with a molecular mass of 49,600 Daltons and an isoelectric point of 5.7. A BLAST search revealed that IRX1 contains two highly conserved domains: a homeodomain and a characteristic IRO motif of unknown function.[22] The homeodomain belongs to the TALE (three amino acid loop extension) class of homeodomains, and is characterized by the addition of three extra amino acids between the first and second helix of three alpha helices that comprise the domain.[23] The presence of this well characterized homeodomain strongly suggests that IRX1 acts as a transcription factor. This is further supported by the predicted localization of IRX1 to the nucleus.[24] The IRO motif is a region downstream of the homeodomain that is found only in members of the Iroquois-class homeodomain proteins, though its function is poorly understood. However, its similarity to an internal region of the Notch receptor protein suggests that it may be involved with protein-protein interaction.[3] In addition to these two characteristic domains, IRX1 contains a third domain from the HARE-HTH superfamily[25] fused to the C-terminal end of the homeodomain.[26] This domain adopts a winged helix-turn-helix fold predicted to bind DNA, and is thought to play a role in recruiting effector activities to DNA.[25] Several forms of post-translational modification are predicted, including SUMOylation, C-mannosylation, and phosphorylation, using bioinformatics tools from ExPASy.[27] Bioinformatic analysis of IRX1 with the NetPhos tool predicted 71 potential phosphorylation sites throughout the protein.[28]

Protein Interactions

Potential protein interacting partners for IRX1 were found using computational tools. The STRING database lists nine putative interacting partners supported by text mining evidence, though closer analysis of the results shows little support for most of these predicted interactions.[29] However, it is possible that one of these proteins, CDKN1A, is involved in the predicted regulation of IRX1 by E2F cell cycle regulators.[16][29]

Conservation

Orthologs

IRX1 has a high degree of conservation across vertebrate and invertebrate species. The entire protein is more fully conserved through vertebrate species, while only the homeodomain and IRO motif are conserved in more distant homologs.[8] Homologous sequences were found in species as distantly related to humans as the pig roundworm Ascaris suum, from the family Ascarididae, using BLAST and the ALIGN tool through the San Diego Super Computer Biology Workbench.[22] The following is a table describing the evolutionary conservation of IRX1.

Genus Species Organism Common Name Divergence from Humans (MYA) [30] NCBI Protein Accession Number Sequence Identity [22] Protein Length Common Gene Name
Homo sapiens[26] Humans -- NP_077313 100% 480 IRX-1
Pongo abelii[31] Sumatran Orangutan 15.7 XP_002815448 99% 480 IRX-1
Bos taurus[32] Cattle 94.2 XP_002696496 92.3% 476 IRX-1
Mus musculus[33] House Mouse 92.3 NP_034703 91.5% 480 IRX-1
Rattus norvegicus[34] Brown rat 92.3 NP_001100801 90.4% 480 IRX-1
Gallus gallus[35] Red Junglefowl 296 NP_001025509 72.9% 467 IRX-1
Xenopus tropicalis[36] Western clawed frog 371.2 NP_001188351 68% 467 IRX-1
Latimeria chalumnae[37] West Indian Ocean coelacanth 441.9 XP_006002089 65.1% 460 Irx-1-A-like isoform X1
Danio rerio[38] Zebrafish 400.1 NP_997067 61.1% 426 Irx-1 isoform 1
Taeniopygia guttata[39] Zebra finch 296 XP_002189063 59.7% 400 Irx-1-A-like
Astyanax mexicanus[40] Mexican tetra 400.1 XP_007254591.1 58% 450 IRX-1
Ophiophagus hannah[41] King cobra 296 ETE68928 54.5% 387 Irx-1-A partial
Ovis aries[42] Sheep 94.2 XP_004017207 43.3% 260 IRX-1
Condylura cristata[43] Star-nosed mole 94.2 XP_004678440 41.7% 342 IRX-1
Branchiostoma floridae[44] Lancelet 713.2 ACF10237.1 35.5% 461 Iroquois A isoform 1
Strongylocentrotus purpuratus[45] Purple sea urchin 742.9 NP_001123285 31.7% 605 Iroquois homeobox A
Ascaris suum[46] Pig roundworm 937.5 F1KXE6 29% 444 IRX-1
Caenorhabditis elegans[47] Nematode roundworm 937.5 NP_492533.2 28.6% 377 IRX-1
Drosophila melanogaster[48] Fruit fly 782.7 NP_524045 27% 717 Araucan isoform A

Paralogs

IRX1 is one of six members of the Iroquois-class homeodomain proteins found in humans: IRX2, IRX3, IRX4, IRX5, and IRX6. IRX1, IRX2, and IRX4 are found on human chromosome 5, and their orientation corresponds to that of IRX3, IRX5, and IRX6 found on human chromosome 16.[3] It is thought that the genomic organization of IRO genes in conserved gene clusters allows for coregulation and enhancer sharing during development.

References

  1. 1 2 3 4 5 "Entrez Gene: iroquois homeobox 1".
  2. ↑ Ogura K, Matsumoto K, Kuroiwa A, Isobe T, Otoguro T, Jurecic V, Baldini A, Matsuda Y, Ogura T (2001). "Cloning and chromosome mapping of human and chicken Iroquois (IRX) genes". Cytogenet. Cell Genet. 92 (3–4): 320–5. doi:10.1159/000056921. PMID 11435706.
  3. 1 2 3 4 Cavodeassi F, Modolell J, Gómez-Skarmeta JL (2001). "The Iroquois family of genes: from body building to neural patterning" (PDF). Development 128 (15): 2847–55. PMID 11532909.
  4. ↑ Bennett KL, Karpenko M, Lin MT, Claus R, Arab K, Dyckhoff G, Plinkert P, Herpel E, Smiraglia D, Plass C (2008). "Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma". Cancer Res. 68 (12): 4494–9. doi:10.1158/0008-5472.CAN-07-6509. PMID 18559491.
  5. ↑ Marcinkiewicz KM, Gudas LJ (2014). "Altered epigenetic regulation of homeobox genes in human oral squamous cell carcinoma cells". Exp. Cell Res. 320 (1): 128–43. doi:10.1016/j.yexcr.2013.09.011. PMID 24076275.
  6. ↑ Guo X, Liu W, Pan Y, Ni P, Ji J, Guo L, Zhang J, Wu J, Jiang J, Chen X, Cai Q, Li J, Zhang J, Gu Q, Liu B, Zhu Z, Yu Y (2010). "Homeobox gene IRX1 is a tumor suppressor gene in gastric carcinoma". Oncogene 29 (27): 3908–20. doi:10.1038/onc.2010.143. PMID 20440264.
  7. ↑ Park SH, Kim SK, Choe JY, Moon Y, An S, Park MJ, Kim DS (2013). "Hypermethylation of EBF3 and IRX1 genes in synovial fibroblasts of patients with rheumatoid arthritis". Mol. Cells 35 (4): 298–304. doi:10.1007/s10059-013-2302-0. PMC 3887890. PMID 23456299.
  8. 1 2 Kerner P, Ikmi A, Coen D, Vervoort M (April 15, 2009). "Evolutionary history of the iroquois/Irx genes in metazoans.". BMC Evolutionary Biology 9 (74): 74. doi:10.1186/1471-2148-9-74. PMC 2674049. PMID 19368711. Retrieved May 2014.
  9. ↑ Choy SW, Cheng CW, Lee ST, Li VW, Hui MN, Hui CC, Liu D, Cheng SH (Dec 2010). "A cascade of irx1a and irx2a controls shh expression during retinogenesis.". Developmental Dynamics 239 (12): 3204–3214. doi:10.1002/dvdy.22462. PMID 21046643. Retrieved March 2014.
  10. ↑ Cheng CW, Yan CH, Choy SW, Hui MN, Hui CC, Cheng SH (Sep 2007). "Zebrafish homologue irx1a is required for the differentiation of serotonergic neurons.". Developmental Dynamics 236 (9): 2661–2667. doi:10.1002/dvdy.21272. PMID 17685478. Retrieved February 2014.
  11. ↑ Becker MB, Zülch A, Bosse A, Gruss P (Aug 2001). "Irx1 and Irx2 expression in early lung development.". Mechanisms of Development 106 (1-2): 155–158. doi:10.1016/S0925-4773(01)00412-9. PMID 11472847. Retrieved March 2014.
  12. ↑ Bosse A, Zülch A, Becker MB, Torres M, Gómez-Skarmeta JL, Modolell J, Gruss P (Dec 1997). "Identification of the vertebrate Iroquois homeobox gene family with overlapping expression during early development of the nervous system.". Mechanisms of Development 69 (1-2): 169–181. doi:10.1016/S0925-4773(97)00165-2. PMID 9486539. Retrieved April 2014.
  13. ↑ Christoffels VM, Keijser AG, Houweling AC, Clout DE, Moorman AF (Aug 15, 2000). "Patterning the embryonic heart: identification of five mouse Iroquois homeobox genes in the developing heart.". Developmental Biology 224 (2): 263–274. doi:10.1006/dbio.2000.9801. PMID 10926765. Retrieved April 2014.
  14. ↑ Díaz-Hernández ME, Bustamante M, Galván-Hernández CI, Chimal-Monroy J (March 11, 2013). "Irx1 and Irx2 are coordinately expressed and regulated by retinoic acid, TGFβ and FGF signaling during chick hindlimb development.". PLoS ONE 8 (3): e58549. doi:10.1371/journal.pone.0058549. PMC 3594311. PMID 23505533. Retrieved May 2014.
  15. ↑ "NCBI Nucleotide: IRX1". Retrieved January 2014.
  16. 1 2 3 "El Dorado". Genomatix. Retrieved March 2014.
  17. ↑ "BioGPS: IRX1". Retrieved 17 May 2014.
  18. 1 2 "GeneCards: IRX1". Retrieved 17 May 2014.
  19. ↑ "GEO Profile: IRX1". Retrieved March 2014.
  20. ↑ Numoto M, Yokoro K, Koshi J (March 24, 1999). "ZF5, which is a Kruppel-type transcriptional repressor, requires the zinc finger domain for self-association.". Biochemical and Biophysical Research Communications 256 (3): 573–578. doi:10.1006/bbrc.1999.0375. PMID 10080939. Retrieved May 17, 2014.
  21. ↑ "Allen Brain Atlas". Retrieved March 2014.
  22. 1 2 3 "IRX1 Analysis". Biology Workbench. San Diego Supercomputing Center- University of California San Diego. Retrieved 8 May 2014.
  23. ↑ Bürglin TR (1997). "Analysis of TALE superclass homeobox genes (MEIS, PBC, KNOX, Iroquois, TGIF) reveals a novel domain conserved between plants and animals". Nucleic Acids Res. 25 (21): 4173–80. doi:10.1093/nar/25.21.4173. PMC 147054. PMID 9336443.
  24. ↑ "Expasy: Psort". Retrieved 18 May 2014.
  25. 1 2 "The HARE-HTH and associated domains: novel modules in the coordination of epigenetic DNA and protein modifications.". Retrieved 17 May 2014.
  26. 1 2 "NCBI Protein: IRX1". Retrieved 18 May 2014.
  27. ↑ "ExPASy: Bioinformatics Resource Portal". Retrieved 18 May 2014.
  28. ↑ "NetPhos". Retrieved 18 May 2014.
  29. 1 2 "STRING Database". Retrieved 5 May 2014.
  30. ↑ "Time Tree".
  31. ↑ "NCBI Nucleotide: XP_002815448". Retrieved 18 May 2014.
  32. ↑ "NCBI Nucleotide: XP_002696496". Retrieved 18 May 2014.
  33. ↑ "NCBI Nucleotide: NP_034703". Retrieved 18 May 2014.
  34. ↑ "NCBI Nucleotide: NP_001100801". Retrieved 18 May 2014.
  35. ↑ "NCBI Nucleotide: NP_001025509". Retrieved 18 May 2014.
  36. ↑ "NCBI Nucleotide: NP_001188351". Retrieved 18 May 2014.
  37. ↑ "NCBI Nucleotide: XP_006002089". Retrieved 18 May 2014.
  38. ↑ "NCBI Nucleotide: NP_997067". Retrieved 18 May 2014.
  39. ↑ "NCBI Nucleotide: XP_002189063". Retrieved 18 May 2014.
  40. ↑ "NCBI Nucleotide: XP_007254591.1". Retrieved 18 May 2014.
  41. ↑ "NCBI Nucleotide: ETE68928". Retrieved 18 May 2014.
  42. ↑ "NCBI Nucleotide: XP_004017207". Retrieved 18 May 2014.
  43. ↑ "NCBI Nucleotide: XP_004678440". Retrieved 18 May 2014.
  44. ↑ "NCBI Nucleotide: ACF10237.1". Retrieved 18 May 2014.
  45. ↑ "NCBI Nucleotide: NP_001123285". Retrieved 18 May 2014.
  46. ↑ "UniProt: F1KXE6". Retrieved 18 May 2014.
  47. ↑ "NCBI Nucleotide: NP_492533.2". Retrieved 18 May 2014.
  48. ↑ "NCBI Nucleotide: NP_524045". Retrieved 18 May 2014.

Further reading

  • Lam CY, Tam PO, Fan DS, Fan BJ, Wang DY, Lee CW, Pang CP, Lam DS (2008). "A genome-wide scan maps a novel high myopia locus to 5p15". Invest. Ophthalmol. Vis. Sci. 49 (9): 3768–78. doi:10.1167/iovs.07-1126. PMID 18421076. 
  • Cirulli ET, Kasperaviciūte D, Attix DK, Need AC, Ge D, Gibson G, Goldstein DB (2010). "Common genetic variation and performance on standardized cognitive tests". European Journal of Human Genetics 18 (7): 815–20. doi:10.1038/ejhg.2010.2. PMC 2987367. PMID 20125193. 
  • Trynka G, Zhernakova A, Romanos J, Franke L, Hunt KA, Turner G, Bruinenberg M, Heap GA, Platteel M, Ryan AW, de Kovel C, Holmes GK, Howdle PD, Walters JR, Sanders DS, Mulder CJ, Mearin ML, Verbeek WH, Trimble V, Stevens FM, Kelleher D, Barisani D, Bardella MT, McManus R, van Heel DA, Wijmenga C (2009). "Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling". Gut 58 (8): 1078–83. doi:10.1136/gut.2008.169052. PMID 19240061. 
  • Bonaldo MF, Lennon G, Soares MB (1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548. 
  • Lewis MT, Ross S, Strickland PA, Snyder CJ, Daniel CW (1999). "Regulated expression patterns of IRX-2, an Iroquois-class homeobox gene, in the human breast". Cell Tissue Res. 296 (3): 549–54. doi:10.1007/s004410051316. PMID 10370142. 
  • Bennett KL, Karpenko M, Lin MT, Claus R, Arab K, Dyckhoff G, Plinkert P, Herpel E, Smiraglia D, Plass C (2008). "Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma". Cancer Res. 68 (12): 4494–9. doi:10.1158/0008-5472.CAN-07-6509. PMID 18559491. 

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