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Gene Review

IKZF1  -  IKAROS family zinc finger 1 (Ikaros)

Homo sapiens

Synonyms: DNA-binding protein Ikaros, Hs.54452, IK1, IKAROS, Ikaros family zinc finger protein 1, ...
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Discovery of Ikaros

The Ikaros protein was discovered in 1991 [1], and the murine gene (Ikzf1) was first cloned in 1992 [2] (see entry for the murine Ikzf1 gene). The murine and the human genes are highly homologous, however, the human IKZF1 gene encodes an alternatively spliced exon that is not found in the mouse Ikaros gene (Ikzf1) [3]. Ikaros is the founding member of the Ikaros family of transcription factors, which includes Helios (IKZF2), Aiolos (IKZF3), Eos (IKZF4) and Pegasus (IKZF5).


Disease relevance of IKZF1

  • Ikaros is an important tumor suppressor in the lymphoid lineage in both mice and humans. While Ikaros mutant mice develop spontaneous thymic lymphoma, with the tumor suppressor function dependent on the fourth DNA-binding zinc finger (ZnF4) [4], Ikaros tumor suppressor function in human leukemia is most recognized in the B-cell lineage [5][6]

High impact information on IKZF1

  • Here we found that mice lacking finger 1 or finger 4 of Ikaros exhibited distinct subsets of the hematological defects of Ikaros-null mice [4].
  • Some factors that control early lymphoid development are discussed, including IL-7 and the Ikaros transcription factors [12].
  • The predicted protein sequence has two potential nuclear localization signals and an unusual combination of different zinc-finger motifs, including IKAROS-like and GATA-binding sequences [13].
  • The Ikaros-dependent down-regulation event and the observed chromatin alterations appear to precede pericentromeric repositioning [14].
  • Ikaros is a unique regulator of lymphopoiesis that associates with pericentromeric heterochromatin and has been implicated in heritable gene inactivation [14].
  • Current models propose that the functions of Ikaros should be disrupted by a small isoform that retains the dimerization domain and lacks the DNA-binding domain [14].

Chemical compound and disease context of IKZF1


Biological context of IKZF1


Anatomical context of IKZF1


Associations of IKZF1 with chemical compounds

  • The activation of FAAH by progesterone was paralleled by a decrease (down to 60%) of the cellular levels of anandamide and involved increased nuclear levels of the transcription factor Ikaros [19].
  • We identified a single nucleotide polymorphism (SNP) affecting the third base of the triplet codon for a proline (CCC or CCA) in the highly conserved bipartite activation region (viz, A or C at position 1002 numbering from the translation start site of Ik-1) within our Ikaros clones [20].
  • Electromobility shift assay revealed that dexamethasone abolished the binding of nuclear transcription factors to the Ikaros binding site and reduced AP-1 binding activity [23].
  • Consistent with this, there was a time-dependent increase in colocalization between IK1 and the lipid raft ganglioside GM1 on the plasma membrane, which subsequently decreased with volume recovery [24].
  • The negative inotropic effect of ACh in ventricular muscle is associated with a reduction of Isi; there is no important effect of ACh on IK1 in ventricular muscle [25].

Physical interactions of IKZF1


Regulatory relationships of IKZF1


Other interactions of IKZF1


Analytical, diagnostic and therapeutic context of IKZF1


  1. LyF-1, a transcriptional regulator that interacts with a novel class of promoters for lymphocyte-specific genes. Lo, K., Landau, N.R., Smale, S.T. Mol. Cell. Biol. (1991) [Pubmed]
  2. Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment. Georgopoulos, K., Moore, D.D., Derfler, B. Science. (1992) [Pubmed]
  3. Cutting edge: predominant expression of a novel Ikaros isoform in normal human hemopoiesis. Payne, K.J., Nicolas, J.H., Zhu, J.Y., Barsky, L.W., Crooks, G.M. J. Immunol. (2001) [Pubmed]
  4. Selective regulation of lymphopoiesis and leukemogenesis by individual zinc fingers of Ikaros. Schjerven, H., McLaughlin, J., Arenzana, T.L., Frietze, S., Cheng, D., Wadsworth, S.E., Lawson, G.W., Bensinger, S.J., Farnham, P.J., Witte, O.N., Smale, S.T. Nat. Immunol. (2013) [Pubmed]
  5. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Mullighan, C.G., Miller, C.B., Radtke, I., Phillips, L.A., Dalton, J., Ma, J., White, D., Hughes, T.P., Le Beau, M.M., Pui, C.H., Relling, M.V., Shurtleff, S.A., Downing, J.R. Nature. (2008) [Pubmed]
  6. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. Mullighan, C.G., Su, X., Zhang, J., Radtke, I., Phillips, L.A., Miller, C.B., Ma, J., Liu, W., Cheng, C., Schulman, B.A., Harvey, R.C., Chen, I.M., Clifford, R.J., Carroll, W.L., Reaman, G., Bowman, W.P., Devidas, M., Gerhard, D.S., Yang, W., Relling, M.V., Shurtleff, S.A., Campana, D., Borowitz, M.J., Pui, C.H., Smith, M., Hunger, S.P., Willman, C.L., Downing, J.R. N. Engl. J. Med. (2009) [Pubmed]
  7. Acute lymphoblastic leukemia in a patient with Greig cephalopolysyndactyly and interstitial deletion of chromosome 7 del(7)(p11.2 p14) involving the GLI3 and ZNFN1A1 genes. Mendoza-Londono, R., Kashork, C.D., Shaffer, L.G., Krance, R., Plon, S.E. Genes Chromosomes Cancer (2005) [Pubmed]
  8. Expression of dominant-negative and mutant isoforms of the antileukemic transcription factor Ikaros in infant acute lymphoblastic leukemia. Sun, L., Heerema, N., Crotty, L., Wu, X., Navara, C., Vassilev, A., Sensel, M., Reaman, G.H., Uckun, F.M. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  9. High frequency of Ikaros isoform 6 expression in acute myelomonocytic and monocytic leukemias: implications for up-regulation of the antiapoptotic protein Bcl-XL in leukemogenesis. Yagi, T., Hibi, S., Takanashi, M., Kano, G., Tabata, Y., Imamura, T., Inaba, T., Morimoto, A., Todo, S., Imashuku, S. Blood (2002) [Pubmed]
  10. The Ikaros gene, a central regulator of lymphoid differentiation, fuses to the BCL6 gene as a result of t(3;7)(q27;p12) translocation in a patient with diffuse large B-cell lymphoma. Hosokawa, Y., Maeda, Y., Ichinohasama, R., Miura, I., Taniwaki, M., Seto, M. Blood (2000) [Pubmed]
  11. Adult acute myeloid leukemia cells do not express nonfunctional Ikaros isoforms. Nishii, K., Katayama, N., Shiku, H. Blood (2002) [Pubmed]
  12. Early T lymphocyte progenitors. Shortman, K., Wu, L. Annu. Rev. Immunol. (1996) [Pubmed]
  13. Mutations in a new gene, encoding a zinc-finger protein, cause tricho-rhino-phalangeal syndrome type I. Momeni, P., Glöckner, G., Schmidt, O., von Holtum, D., Albrecht, B., Gillessen-Kaesbach, G., Hennekam, R., Meinecke, P., Zabel, B., Rosenthal, A., Horsthemke, B., Lüdecke, H.J. Nat. Genet. (2000) [Pubmed]
  14. Down-regulation of TDT transcription in CD4(+)CD8(+) thymocytes by Ikaros proteins in direct competition with an Ets activator. Trinh, L.A., Ferrini, R., Cobb, B.S., Weinmann, A.S., Hahm, K., Ernst, P., Garraway, I.P., Merkenschlager, M., Smale, S.T. Genes Dev. (2001) [Pubmed]
  15. Chronic angiotensin II stimulation in the heart produces an acquired long QT syndrome associated with IK1 potassium current downregulation. Domenighetti, A.A., Boixel, C., Cefai, D., Abriel, H., Pedrazzini, T. J. Mol. Cell. Cardiol. (2007) [Pubmed]
  16. Eos and pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities. Perdomo, J., Holmes, M., Chong, B., Crossley, M. J. Biol. Chem. (2000) [Pubmed]
  17. Vasoactive intestinal peptide receptor-1 (VPAC-1) is a novel gene target of the hemolymphopoietic transcription factor Ikaros. Dorsam, G., Goetzl, E.J. J. Biol. Chem. (2002) [Pubmed]
  18. STAT4 is a target of the hematopoietic zinc-finger transcription factor Ikaros in T cells. Yap, W.H., Yeoh, E., Tay, A., Brenner, S., Venkatesh, B. FEBS Lett. (2005) [Pubmed]
  19. Progesterone activates fatty acid amide hydrolase (FAAH) promoter in human T lymphocytes through the transcription factor Ikaros. Evidence for a synergistic effect of leptin. Maccarrone, M., Bari, M., Di Rienzo, M., Finazzi-Agrò, A., Rossi, A. J. Biol. Chem. (2003) [Pubmed]
  20. Expression of aberrantly spliced oncogenic ikaros isoforms in childhood acute lymphoblastic leukemia. Sun, L., Goodman, P.A., Wood, C.M., Crotty, M.L., Sensel, M., Sather, H., Navara, C., Nachman, J., Steinherz, P.G., Gaynon, P.S., Seibel, N., Vassilev, A., Juran, B.D., Reaman, G.H., Uckun, F.M. J. Clin. Oncol. (1999) [Pubmed]
  21. Ikaros is expressed in human extravillous trophoblasts and involved in their migration and invasion. Yamamoto, E., Ito, T., Abe, A., Sido, F., Ino, K., Itakura, A., Mizutani, S., Dovat, S., Nomura, S., Kikkawa, F. Mol. Hum. Reprod. (2005) [Pubmed]
  22. Identification of two Ikaros-like transcription factors in lamprey. Mayer, W.E., O'Huigin, C., Tichy, H., Terzic, J., Saraga-Babic, M. Scand. J. Immunol. (2002) [Pubmed]
  23. Down-regulation of human granzyme B expression by glucocorticoids. Dexamethasone inhibits binding to the Ikaros and AP-1 regulatory elements of the granzyme B promoter. Wargnier, A., Lafaurie, C., Legros-Maïda, S., Bourge, J.F., Sigaux, F., Sasportes, M., Paul, P. J. Biol. Chem. (1998) [Pubmed]
  24. Ca2+-activated IK1 Channels Associate with Lipid Rafts upon Cell Swelling and Mediate Volume Recovery. Barfod, E.T., Moore, A.L., Roe, M.W., Lidofsky, S.D. J. Biol. Chem. (2007) [Pubmed]
  25. Development of different electrophysiological mechanisms for muscarinic inhibition of atria and ventricles. Pappano, A.J., Inoue, D. Fed. Proc. (1984) [Pubmed]
  26. Ikaros-CtIP interactions do not require C-terminal binding protein and participate in a deacetylase-independent mode of repression. Koipally, J., Georgopoulos, K. J. Biol. Chem. (2002) [Pubmed]
  27. Ikaros DNA-Binding Proteins as Integral Components of B Cell Developmental-Stage-Specific Regulatory Circuits. Thompson, E.C., Cobb, B.S., Sabbattini, P., Meixlsperger, S., Parelho, V., Liberg, D., Taylor, B., Dillon, N., Georgopoulos, K., Jumaa, H., Smale, S.T., Fisher, A.G., Merkenschlager, M. Immunity (2007) [Pubmed]
  28. An ikaros-containing chromatin-remodeling complex in adult-type erythroid cells. O'Neill, D.W., Schoetz, S.S., Lopez, R.A., Castle, M., Rabinowitz, L., Shor, E., Krawchuk, D., Goll, M.G., Renz, M., Seelig, H.P., Han, S., Seong, R.H., Park, S.D., Agalioti, T., Munshi, N., Thanos, D., Erdjument-Bromage, H., Tempst, P., Bank, A. Mol. Cell. Biol. (2000) [Pubmed]
  29. Ikaros interactions with CtBP reveal a repression mechanism that is independent of histone deacetylase activity. Koipally, J., Georgopoulos, K. J. Biol. Chem. (2000) [Pubmed]
  30. BCR-ABL1 induces aberrant splicing of IKAROS and lineage infidelity in pre-B lymphoblastic leukemia cells. Klein, F., Feldhahn, N., Herzog, S., Sprangers, M., Mooster, J.L., Jumaa, H., Müschen, M. Oncogene (2006) [Pubmed]
  31. Overexpression of dominant-negative Ikaros 6 protein is restricted to a subset of B common adult acute lymphoblastic leukemias that express high levels of the CD34 antigen. Tonnelle, C., Imbert, M.C., Sainty, D., Granjeaud, S., N'Guyen, C., Chabannon, C. Hematol. J. (2003) [Pubmed]
  32. Ap-2 and Ikaros regulate transcription of human placental leucine aminopeptidase/oxytocinase gene. Ito, T., Nomura, S., Okada, M., Katsumata, Y., Kikkawa, F., Rogi, T., Tsujimoto, M., Mizutani, S. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  33. Overexpression of novel short isoforms of Helios in a patient with T-cell acute lymphoblastic leukemia. Nakase, K., Ishimaru, F., Fujii, K., Tabayashi, T., Kozuka, T., Sezaki, N., Matsuo, Y., Harada, M. Exp. Hematol. (2002) [Pubmed]
  34. A molecular dissection of the repression circuitry of Ikaros. Koipally, J., Georgopoulos, K. J. Biol. Chem. (2002) [Pubmed]
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