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FLASH GENE
Symbol IKZF1 contributors: mct - updated : 27-03-2018
HGNC name IKAROS family zinc finger 1 (Ikaros)
HGNC id 13176
Location 7p12.2      Physical location : 50.344.377 - 50.472.796
Synonym name
  • CLL-associated antigen KW-6
  • zinc finger protein, subfamily 1A, 1 (Ikaros)
  • DNA-binding protein Ikaros
  • lymphoid transcription factor LyF-1
  • Synonym symbol(s) LYF-1, IK1, IKAROS, hIk-1, ZNFN1A1, PRO0758, Hs.54452, LyF-1, PPP1R92
    DNA
    TYPE functioning gene
    STRUCTURE 28.57 kb     5 Exon(s)
    regulatory sequence Promoter
    Binding site   transcription factor
    text structure
  • binding sequences found in the promoters of both CD4 and CD2 genes
  • IKZF1/Ets binding site within a promoter sub-region that was highly conserved
  • MAPPING cloned Y linked N status provisional
    regionally located located near the EGFR gene
    RNA
    TRANSCRIPTS type messenger
    text
  • exons 47 are alternatively spliced, generating Ikaros isoforms with different DNA binding abilities (PMID: 20888815)
  • alternative splicing can generate multiple Ikaros isoforms that lack variable numbers of internal exon (PMID: 21329675)
  • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    5 splicing 6202 57.5 519 - 2011 21329675
    3 splicing 5956 - 432 - 2011 21329675
    also called IK3
    4 splicing 5634 - 376 - 2011 21329675
    also called IK5
    4 splicing 6091 - 477 - 2011 21329675
    also called IK2
    7 - 6164 - 477 - 2011 21329675
    6 - 5772 - 422 - 2011 21329675
    also called IK4
    - - 5830 - 389 - 2011 21329675
  • also called IK6
  • playing a key role in human B-cell malignancies through the dominant-negative isoform IK6
  • implicated in pituitary tumorsigenesis through its actions on FGFR4 promoter acetylation
  • 7 - 6029 - 432 - 2011 21329675
  • Ik-2
  • 5 - 5646 - 380 - 2011 21329675
    6 - 5708 - 390 - 2011 21329675
  • Ik-4
  • 3 - 5373 - 289 - 2011 21329675
  • Ik-6
  • 5 - 5638 - 376 - 2011 21329675
  • Ik-7
  • 5 - 5604 - 366 - 2011 21329675
  • Ik-7(del)
  • 4 - 5508 - 334 - 2011 21329675
  • Ik-8
  • 4 - 5478 - 324 - 2011 21329675
  • Ik-8(del)
  • 4 - 1896 - 174 - 2011 21329675
    5 - 806 - 77 - 2011 21329675
    5 - 779 - 77 - 2011 21329675
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    blood / hematopoieticspleen   highly
     thymus   highly
    Lymphoid/Immunelymph node   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    Lymphoid    
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticleukocyte
    Blood/Hematopoieticprogenitor cell Homo sapiens
    cell lineage hematopoietic stem cells, all lymphoid and some myeloid cells
    cell lines
    fluid/secretion lymph
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • four N terminal zinc fingers comprising the DNA binding domain
  • a central DNA-binding domain consisting of four zinc fingers
  • two PEST-like sequences, which have been implicated in proteolysis of proteins by calpains, helping to bind these proteases to their targets
  • a conserved PPP1CC binding motif, RVXF, in the C-terminal end , and a homo- and heterodimerization domain consisting of the two C-terminal zinc fingers
  • conjugated MetalloP
    mono polymer homomer , heteromer , dimer
    HOMOLOGY
    interspecies homolog to murine Ikaros/Znfn1a1
    homolog to C.elegans M03D4.4
    Homologene
    FAMILY
  • zinc finger subfamily 1A
  • IKAROS family
  • CATEGORY transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus,chromatin/chromosome,heterochromosome
    text
  • can target PPP1CC to the nucleus, and a fraction of PPP1CC colocalizes with IKZF1 at pericentromeric heterochromatin (PC-HC)
  • native IKZF1 and SYK are colocalized in both the nucleus and cytoplasm of human cells
  • basic FUNCTION
  • zinc finger protein that is essential for normal hematopoiesis
  • activating the enhancer (delta-A element) of the CD3-delta gene
  • key regulator of hematopoiesis, having an essential role in lymphocyte development, and in regulation of B cell receptor signaling
  • functioning in the specification and the maturation of the lymphocyte
  • playing critical functions in the control of lymphohematopoiesis and immune regulation
  • playing a role in the neuroendocrine system, highlighting a critical contribution to the development of the hypothalamic-pituitary somatotrophic axis
  • acting both as an activator and repressor of transcriptionand may act together with other transcription factors to modulate promoter activity
  • carry out critical functions during lymphocyte development
  • required for normal lymphoid development
  • may function as a typical transcription factor and may function more broadly, perhaps in the formation of silent and active chromatin structures
  • regulate the pre-BCR component lambda5 in a stage-specific manner
  • its function is controlled by the CK2 and PPP1CC pathways and a balance between these two signal transduction pathways is essential for normal cellular function and for the prevention of malignant transformation
  • zinc finger protein that is involved in gene regulation and chromatin remodeling
  • in the nucleus, forms complexes with ubiquitin, providing evidence that IKZF1 degradation involves the ubiquitin/proteasome pathway
  • required for the normal development of lymphocytes and other blood cell lineages, and have an important role in haematopoietic malignancies
  • Ikaros family members are critical for a functional immune system that confers protection against invading pathogens, while minimising the risk of leukaemic transformation, immune pathology, and autoimmunity
  • is essential in both the myeloid and lymphoid development
  • IRF5-IKZF1 axis is a critical modulator of IgG2a/c class switching
  • zinc finger-containing DNA-binding protein that plays a pivotal role in immune homeostasis through transcriptional regulation of the earliest stages of lymphocyte ontogeny and differentiation
  • important functional interplay between Ikaros, GATA factors, and the NOTCH signaling pathway in specification and homeostasis of the megakaryocyte lineage
  • in multipotent, hematopoietic progenitors, IKZF1 supports transcriptional priming of genes promoting lymphocyte differentiation
  • novel roles of IKAROS in regulating normal human hematopoietic cells
  • IKZF1 and HDAC1 regulate the epigenetic signature in leukemia, via regulation of KDM5B transcription
  • functions as a guardian of B-1 lymphoid pattern, and its absence directs the differentiation of B-1 cells into phagocytes
  • is a fundamental regulator of Polycomb repressive complex 2 (PRC2) function in developing T cells
  • IKZF1 is required to limit B1 cell homeostasis in the adult
  • IKZF1 and FOXP1 are transcription factors that play key roles in normal lymphopoiesis and lymphoid malignancies
  • is a haematopoietic transcription factor required for mammalian B-cell development
  • CELLULAR PROCESS cell life, differentiation
    nucleotide, chromatin organization, remodeling
    nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS development
    text lymphoid mesoderm development; transcription activator
    PATHWAY
    metabolism
    signaling
    a component
  • integral component of chromatin-remodeling complexes
  • homo or heterodimerizing with either other member of the family
  • INTERACTION
    DNA
  • binding to the enhancer (delta-A element) of the CD3-delta gene
  • binding to a critical control element in the terminal deoxynucleotdyltransferase (TDT) promoter
  • binding to the promoter for other genes expressed during early stages of B and T cell development
  • RNA
    small molecule metal binding,
  • Zn2+
  • protein
  • interacts with a critical control element in the tdt (terminal deoxynucleotidyltransferase) promoter as well as with the promoters for other genes expressed during early stages of B and T cell development
  • combinatorial effect of Ikaros and GATA1 impairs close proximity between the locus control region and the gamma-globin genes and might represent an important mechanism of gene regulation during hematopoiesis
  • interacts with protein phosphatase 1 (PPP1CC) via a conserved PP1 binding motif, RVXF, in the C-terminal end of the IKZF1 protein
  • IKZF3 and IKZF1 bind to the MYC promoter and directly suppress MYC expression in pre-B cells
  • downregulation of MYC by IKZF1 and IKZF3 is necessary for the induction of CDKN1B and downregulation of CCND3
  • IKZF1 is a critical BMI1 target that prevents premature lineage specification of hematopoietic stem cell (HSC)
  • CTBP1 interacts with Ikaros and modulates pituitary tumor cell survival and response to hypoxia
  • SYK is a partner and posttranslational regulator of IKZF1, and SYK-induced IKZF1 activation is essential for its nuclear localization and optimal transcription factor function
  • BTK is a partner and posttranslational regulator of IKZF1, a zinc finger-containing DNA-binding protein that plays a pivotal role in immune homeostasis
  • is a suppressor of basophil differentiation under steady-state conditions and that it acts by regulating permissive chromatin modifications of CEBPA
  • is a central regulator of IL7 signaling and pre-B cell development
  • IKZF1 represses transcription of the histone H3K4 demethylase, JARID1B (KDM5B)
  • CRBN was associated with IKZF1 protein, and the N-terminal region of CRBN was required for IKZF1 binding
  • CRBN binds to IKZF1 via its N-terminal region and regulates transcriptional activities of IKZF1 and its downstream target, enkephalin
  • GPR132 is a potential modulator of the cell cycle in IKZF1-deleted B-acute lymphoblastic leukemia (ALL)
  • ability of IKZF1 to bind the ADAMTS10 promoter, influencing its transfected activity, and inducing endogenous gene expression
  • IKZF1 directly binds the DNM2 promoter and suppresses DNM2 expression
  • STAT3 and the Ikaros zinc finger transcription factors IKZF3, IKZF1 cooperate to regulate BCL66 expression
  • RGAG4 is an IKZF1 target in the pituitary
  • dendritic cell development and function are regulated by IKZF1
  • cell & other
    REGULATION
    Phosphorylated by SYK that phosphorylates IKZF1 at serine phosphorylation sites S358 and S361, thereby augmenting its nuclear localization and sequence-specific DNA binding activity
    Other regulated through multiple histone modifications and deoxyribonucleic acid methylation in the pituitary (Zhu 2007)
    regulation by phosphorylation (CK2 kinase phosphorylation determines its ability to bind DNA and exert cell cycle control as well as its subcellular localization)
    degradation of Ikaros isoform 1,(IK1) protein via the proteasome system is an early event during apoptosis progression()
    sumoylation may be important likely in modulating the tumor suppressor function of IKZF1
    is regulated by both epigenetic and transcriptional factors that target its enhancers in both redundant and specific fashions to provide an expression profile supportive of normal lymphoid lineage progression and homeostasis
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral fusion      
    to BCL6 in diffuse large B cell lymphoma in translocation t(3;7) (q27;p12)
    tumoral     --over  
    in blast crisis of chronic myelogenous leukemia and B-cell acute lymphoblastic leukemia
    tumoral   deletion    
    in acute lymphoblastic leukemia
    tumoral   deletion    
    in BCR-ABL1 acute lymphoblastic leukaemia, deletion resulted in haploinsufficiency, expression of a dominant-negative Ikaros isoform, or the complete loss of Ikaros expression
    tumoral       loss of function
    associated with the development of infant T-cell acute lymphoblastic leukemia (ALL), adult B cell ALL, myelodysplastic syndrome, acute myeloid leukemia, and adult and juvenile chronic myelogenous leukemia
    constitutional     --over  
    increases apoptosis
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • Ikaros-deficient animals fail to develop B cells and display a T-cell malignancy, which is correlated with altered Notch signaling