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"Ikaros transcription factor" redirects here. For other uses, see Icarus (disambiguation).
IKZF1
Identifiers
Aliases IKZF1, Hs.54452, IK1, IKAROS, LYF1, LyF-1, PPP1R92, PRO0758, ZNFN1A1, CVID13, IKAROS family zinc finger 1
External IDs OMIM: 603023 MGI: 1342540 HomoloGene: 55948 GeneCards: IKZF1
Orthologs
SpeciesHumanMouse
Entrez

10320

22778

Ensembl

ENSG00000185811

ENSMUSG00000018654

UniProt

Q13422

Q03267

RefSeq (mRNA)
RefSeq (protein)

n/a

Location (UCSC) Chr 7: 50.3 – 50.41 Mb Chr 11: 11.64 – 11.72 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

DNA-binding protein Ikaros also known as Ikaros family zinc finger protein 1 is a protein that in humans is encoded by the IKZF1 gene. [5] [6] [7]

Ikaros - transcription factor

Ikaros is a transcription factor that is encoded by the IKZF genes of the Ikaros family zinc finger group. Zinc finger is a small structural motif of protein that allows protein binding to DNA or RNA molecule that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold.

Ikaros displays crucial functions in the hematopoietic system and is a known regulator of immune cells development, mainly in early B cells, CD4+ T cells. Its dysfunction has been linked to the development of chronic lymphocytic leukemia. [8] [9] In particular, Ikaros has been found in recent years to be a major tumor suppressor involved in human B-cell acute lymphoblastic leukemia [8] and that it also has a part in the differentiation and function of individual T helper cells. [10]

Ikaros also has a role during the later stages of B cell development during VDJ recombination in switch class of the antibody isotypes and expression of the B cell receptor. [11]

In Ikaros knockout mice, T cells but not B cells are generated late in mouse development due to late compensatory expression of the related gene Aiolos (IKZF3). [12] Ikaros point mutant mice are embryonic lethal due to anemia; they have severe defects in terminal erythrocyte and granulocyte differentiation, and excessive macrophage formation. [13] SNPs located near the 3' region of IKZF1 in humans have been linked to susceptibility to childhood acute lymphoblastic leukemia (ALL) [14] as well as type 1 diabetes. [15] The two effects appear to be in opposite directions, with the allele marking susceptibility to ALL protecting from T1D and vice versa. [15]

Further evidence shows that Ikaros regulates the development of medullary thymic epithelial cells (mTECs). Conditional deletion of Ikzf1 in thymic epithelial cells by Foxn1- Cre in mice, results in the dysregulation of various mTEC subsets, including the loss of Aire+ mTECs. The loss of Aire (Autoimmune regulator) expressing mTECs also causes global loss of tissue restricted antigens (TRAs) and Aire-dependent mimetic cell populations, with the loss of TRAs eventually leading to breakdown of immune tolerance. [16]

Genes of the Ikaros Zinc Finger Family group

The Ikaros Zinc Finger (IkZF) family of transcription factors are known regulators of hematopoietic cell development and many immune cells including that of CD4+ T cells.

The IkZF family consists of five members: Ikaros (encoded by the gene Ikzf1), Helios ( Ikzf2), Aiolos ( Ikzf3), Eos ( Ikzf4), and Pegasus ( Ikzf5). These factors contain N-terminal zinc finger (ZF) domains, which are responsible for mediating direct interactions with DNA, and C-terminal ZFs, which facilitate homo- and heterodimerization between IkZF family members. [17]

IKZF1 is upregulated in granulocytes, B cells, CD4 and CD8 T cells, and NK cells, and downregulated in erythroblasts, megakaryocytes and monocytes. [18]

Ikaros deficiency

The mutation in the IKZF1 gene can cause dysfunction of the Ikaros transcription factor. The dysfunction affects expression in B cells that can lead to deregulation of the BCR signaling during B cell development and is associated with B cell transformation. The deregulation then can result in low proliferation rate and increased apoptosis of the B cells. The deregulation may be related with lymphoproliferative disorders and different forms of leukemia. [19]

Interactions

IKZF1 has been shown to interact with:

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000185811 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000018654 – Ensembl, May 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. ^ Georgopoulos K, Moore DD, Derfler B (October 1992). "Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment". Science. 258 (5083): 808–12. Bibcode: 1992Sci...258..808G. doi: 10.1126/science.1439790. PMID  1439790.
  6. ^ Hahm K, Ernst P, Lo K, Kim GS, Turck C, Smale ST (November 1994). "The lymphoid transcription factor LyF-1 is encoded by specific, alternatively spliced mRNAs derived from the Ikaros gene". Molecular and Cellular Biology. 14 (11): 7111–23. doi: 10.1128/mcb.14.11.7111. PMC  359245. PMID  7935426.
  7. ^ "Entrez Gene: IKZF1 IKAROS family zinc finger 1 (Ikaros)".
  8. ^ a b Kastner P, Chan S (June 2011). "Role of Ikaros in T-cell acute lymphoblastic leukemia". World Journal of Biological Chemistry. 2 (6): 108–14. doi: 10.4331/wjbc.v2.i6.108. PMC  3135856. PMID  21765975.
  9. ^ Oliveira VC, Lacerda MP, Moraes BB, Gomes CP, Maricato JT, Souza OF, et al. (July 2019). "Deregulation of Ikaros expression in B-1 cells: New insights in the malignant transformation to chronic lymphocytic leukemia". Journal of Leukocyte Biology. 106 (3): 581–594. doi: 10.1002/JLB.MA1118-454R. PMID  31299112. S2CID  196350761.
  10. ^ Powell MD, Read KA, Sreekumar BK, Oestreich KJ (2019). "+ T Helper Cell Differentiation". Frontiers in Immunology. 10: 1299. doi: 10.3389/fimmu.2019.01299. PMC  6563078. PMID  31244845.
  11. ^ Sellars M, Kastner P, Chan S (June 2011). "Ikaros in B cell development and function". World Journal of Biological Chemistry. 2 (6): 132–9. doi: 10.4331/wjbc.v2.i6.132. PMC  3135860. PMID  21765979.
  12. ^ Georgopoulos K, Winandy S, Avitahl N (1997). "The role of the Ikaros gene in lymphocyte development and homeostasis". Annual Review of Immunology. 15: 155–76. doi: 10.1146/annurev.immunol.15.1.155. PMID  9143685.
  13. ^ Papathanasiou P, Perkins AC, Cobb BS, Ferrini R, Sridharan R, Hoyne GF, et al. (July 2003). "Widespread failure of hematolymphoid differentiation caused by a recessive niche-filling allele of the Ikaros transcription factor". Immunity. 19 (1): 131–44. doi: 10.1016/s1074-7613(03)00168-7. PMID  12871645.
  14. ^ Papaemmanuil E, Hosking FJ, Vijayakrishnan J, Price A, Olver B, Sheridan E, et al. (September 2009). "Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia". Nature Genetics. 41 (9): 1006–10. doi: 10.1038/ng.430. PMC  4915548. PMID  19684604.
  15. ^ a b Swafford AD, Howson JM, Davison LJ, Wallace C, Smyth DJ, Schuilenburg H, et al. (March 2011). "An allele of IKZF1 (Ikaros) conferring susceptibility to childhood acute lymphoblastic leukemia protects against type 1 diabetes". Diabetes. 60 (3): 1041–4. doi: 10.2337/db10-0446. PMC  3046822. PMID  21270240.
  16. ^ Sin JH, Sucharov J, Kashyap S, Wang Y, Proekt I, Liu X, Parent AV, Gupta A, Kastner P, Chan S, Gardner JM, Ntranos V, Miller CN, Anderson MS, Schjerven H (2023-10-27). "Ikaros is a principal regulator of Aire+ mTEC homeostasis, thymic mimetic cell diversity, and central tolerance". Science Immunology. 8 (88): eabq3109. doi: 10.1126/sciimmunol.abq3109. ISSN  2470-9468. PMID  37889983. S2CID  264518068.
  17. ^ Powell MD, Read KA, Sreekumar BK, Oestreich KJ (2019-06-06). "+ T Helper Cell Differentiation". Frontiers in Immunology. 10: 1299. doi: 10.3389/fimmu.2019.01299. PMC  6563078. PMID  31244845.
  18. ^ Watkins NA, Gusnanto A, de Bono B, De S, Miranda-Saavedra D, Hardie DL, et al. (May 2009). "A HaemAtlas: characterizing gene expression in differentiated human blood cells". Blood. 113 (19): e1-9. doi: 10.1182/blood-2008-06-162958. PMC  2680378. PMID  19228925.
  19. ^ Oliveira VC, Lacerda MP, Moraes BB, Gomes CP, Maricato JT, Souza OF, et al. (July 2019). "Deregulation of Ikaros expression in B-1 cells: New insights in the malignant transformation to chronic lymphocytic leukemia". Journal of Leukocyte Biology. 106 (3): 581–594. doi: 10.1002/JLB.MA1118-454R. PMID  31299112. S2CID  196350761.
  20. ^ Koipally J, Georgopoulos K (June 2000). "Ikaros interactions with CtBP reveal a repression mechanism that is independent of histone deacetylase activity". The Journal of Biological Chemistry. 275 (26): 19594–602. doi: 10.1074/jbc.M000254200. PMID  10766745.
  21. ^ a b c d Koipally J, Renold A, Kim J, Georgopoulos K (June 1999). "Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes". The EMBO Journal. 18 (11): 3090–100. doi: 10.1093/emboj/18.11.3090. PMC  1171390. PMID  10357820.
  22. ^ a b c d e Koipally J, Georgopoulos K (August 2002). "A molecular dissection of the repression circuitry of Ikaros". The Journal of Biological Chemistry. 277 (31): 27697–705. doi: 10.1074/jbc.M201694200. PMID  12015313.
  23. ^ Kelley CM, Ikeda T, Koipally J, Avitahl N, Wu L, Georgopoulos K, Morgan BA (April 1998). "Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors". Current Biology. 8 (9): 508–15. Bibcode: 1998CBio....8..508K. doi: 10.1016/s0960-9822(98)70202-7. PMID  9560339. S2CID  17835058.
  24. ^ Morgan B, Sun L, Avitahl N, Andrikopoulos K, Ikeda T, Gonzales E, et al. (April 1997). "Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation". The EMBO Journal. 16 (8): 2004–13. doi: 10.1093/emboj/16.8.2004. PMC  1169803. PMID  9155026.
  25. ^ Kim J, Sif S, Jones B, Jackson A, Koipally J, Heller E, et al. (March 1999). "Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes". Immunity. 10 (3): 345–55. doi: 10.1016/s1074-7613(00)80034-5. PMID  10204490.
  26. ^ Honma Y, Kiyosawa H, Mori T, Oguri A, Nikaido T, Kanazawa K, et al. (March 1999). "Eos: a novel member of the Ikaros gene family expressed predominantly in the developing nervous system". FEBS Letters. 447 (1): 76–80. doi: 10.1016/s0014-5793(99)00265-3. PMID  10218586. S2CID  28898354.
  27. ^ Perdomo J, Holmes M, Chong B, Crossley M (December 2000). "Eos and pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities". The Journal of Biological Chemistry. 275 (49): 38347–54. doi: 10.1074/jbc.M005457200. PMID  10978333.
  28. ^ Koipally J, Georgopoulos K (June 2002). "Ikaros-CtIP interactions do not require C-terminal binding protein and participate in a deacetylase-independent mode of repression". The Journal of Biological Chemistry. 277 (26): 23143–9. doi: 10.1074/jbc.M202079200. PMID  11959865.
  29. ^ Katsumura KR, Bresnick EH (April 2017). "The GATA factor revolution in hematology". Blood. 129 (15): 2092–2102. doi: 10.1182/blood-2016-09-687871. PMC  5391619. PMID  28179282.

Further reading

External links

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