Integrative genomic analyses on Ikaros and its expression related to solid cancer prognosis

Abstract

Abstract. Ikaros is a member of the Kruppel family of zinc finger DNA-binding proteins. The Ikaros protein contains two separate regions of zinc-finger domains: 4 DNA-binding zinc fingers near the N-terminus and 2 zinc fingers for proteinprotein interactions near the C-terminus. Here, we identified the Ikaros gene from 14 vertebrate genomes and found Ikaros existed in all kinds of vertebrate including fish, amphibians, birds and mammals. Moreover, except rat and Xenopus tropicalis Ikaros proteins, which lack the first C2H2-type 1 Zinc finger region, all identified Ikaros proteins contain six C2H2-type 1 Zinc finger regions. We found human Ikaros gene showed a predominant expression in the liver, lymph node, thymus, intestine, lung, mammary gland, bone marrow, brain, heart, placenta and prostate. Moreover, four available SNPs disrupted an existing exonic splicing enhancer were identified in Ikaros. Besides the reported acute lymphoblastic leukemia (ALL), the expression of Ikaros was related to the prognosis of 13 cases of cancers including blood cancers, breast, lung, ovarian and skin cancer. Moreover, the relationship between the expression of Ikaros and prognosis varied in different cancers, even in the same cancer from different database. Two tumor-related transcriptional factor (c-Fos and Elk-1) binding sites were identified within the 1.5-kb regions upstream of the transcriptional start site of human Ikaros, which may be involved in the effect of Ikaros in tumors. IntroductionThe Ikaros (IKZF1, Lyf-1) is a member of the Kruppel family of zinc finger DNA-binding proteins 1 (1). The Ikaros protein contains two separate regions of zinc-finger domains: 4 DNA-binding zinc fingers near the N-terminus and 2 zinc fingers for protein-protein interactions near the C-terminus. The human Ikaros gene, located at 7p12, contains seven exons and gives rise to at least eight isoforms by alternative splicing (2). All isoforms share a common C-terminal domain that contains a transcriptional activation domain and two zinc finger motifs required for hetero-or homodimerization and for interactions with other proteins, but these isoforms differ in the number of N-terminal zinc finger motifs. Long isoforms (Ik1 to 3) have at least three zinc fingers which are capable of binding DNA and considered to be functional. Short isoforms (Ik4 to 8) lack two or more zinc-finger domains, so they cannot bind DNA and impair the function of Ikaros proteins in a dominant-negative manner (3-6).Ikaros is a transcription factor, which plays an important role in controlling hematopoietic, particularly lymphoid cell differentiation, proliferation and function by binding upstream regulatory regions of target genes and aiding in their recruitment to pericentromeric heterochromatin (PC-HC) (7). This process leads to either activation or repression of transcription of these target genes by elaborate splicing regulation of Ikaros transcripts (3-6). Accordingly, abnormalities in splicing regulation of Ikaros would lead to significant pathological manifestat...

Direct Protein Interactions Are Responsible for Ikaros-GATA and Ikaros-Cdk9 Cooperativeness in Hematopoietic Cells

“…Thus, in vivo, Ik6 possesses higher binding affinity for Ik1 than for GATA partners. Since dominant-negative Ik isoforms are related to the prognosis of several solid tumors (79) and are frequently overrepresented in malignant hematopoietic cells (80,81), disruption of the combined action of Ik and GATA factors is likely to be highly relevant for neoplastic transformation.…”

Integrative genomic analyses of the histamine H1 receptor and its role in cancer prediction

“…Functional relevant SNPs (single nucleotide polymorphisms) of the human HRH1 gene were identified as previously described (13)(14)(15)21). The SNPs were extracted from Ensembl (http://www.ensembl.org) and NCBI's SNPdb (http://www.…”

“…The assemblies used were human NCBI36, chimpanzee CHIMP2.1, macaque MMUL 1.0, orangutan PPYG2, dog CanFam 2.0, cow Btau_4.0, horse Equ Cab 2, mouse NCBI m37, rat RGSC 3.4, opossum monDom5, chicken WASHUC2, X. tropicalis JGI 4.1, zebrafish Zv8 and fugu FUGU 4.0. The identified putative HRH1 genes were BLASTed against the nr database of GenBank to confirm that the best hits were HRH1 genes (13)(14)(15). Conserved transcription factor-binding sites within the promoter region of the human HRH1 gene were obtained from SABiosciences' proprietary database which combines Text Mining Application and data from the UCSC Genome Browser.…”

Integrative genomic analyses of recepteur d’origine nantais and its prognostic value in cancer

“…Functional relevant SNPs of the human RON gene were identified as previously described (15). The SNPs were extracted from Ensembl (http://www.ensembl.org) and NCBI's SNPdb (http://www.ncbi.nlm.nih.gov).…”

“…The expression profiles for normal human tissues were obtained from GeneAnnot (29) and ArrayExpress (30). Northern analysis of NCBI's uniGene dataset was also extracted (15).…”