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A Tissue-Specific DNA Binding Protein, to Chromosome 11Q24-Q25

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A Tissue-Specific DNA Binding Protein, to Chromosome 11Q24-Q25 GENOMICS 14, 270-274 (1992) Localization of the Gene Encoding RKB (NFRKB), A Tissue-Specific DNA Binding Protein, to Chromosome 11q24-q25 BARBARAS. ADAMS,* KWANYEE LEUNG,* PAUL S. MELTZER,I KATHYA. LEWlS,~ CARYN WAGNER-MCPHERSON,:I: GLEN A. EVANS,:I: AND GARY J. NABEL*'1 *Departments of Internal Medicine and Biological Chemistry, Howard Hughes Medical Institute, t Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0650; and ~Molecular Genetics Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037 Received April 6, 1992; revised June 26, 1992 A KB site has been identified in the enhancer region of Although NF (nuclear factor)-KB binds in vitro to sev- the interleukin-2 receptor a-chain gene (IL-2Ra), dif- eral of the KB regulatory elements found in cellular and fering by 2 of 11 bp from the Ig/HIV KB site (Leung and viral genes, another DNA binding protein, RKB, also Nabel, 1988; Bohnlein et al., 1988; Ruben et al., 1988). binds to a related variant of the KB site that regulates Expression of the inducible IL-2R a-chain in response to interleukin-2 receptor a-chain gene expression, a criti- stimulation by antigen or mitogen produces high-affin- cal event in T cell activation. Southern blot analysis of ity IL-2 receptors on the cell surface. These receptors a human-mouse somatic cell hybrid panel and in situ mediate the physiologic interleukin-2 (IL-2) response hybridization using a fluorescent genomic R~B probe and participate in an autostimulatory IL-2 circuit that have allowed assignment of the RKB gene (NFRKB) to mediates clonal expansion of activated T cells (for re- llq24-q25. The NFRKB locus is in close proximity to view, see Waldmann, 1989). IL-2Ra expression is regu- the chromosomal breakpoint implicated in Ewing sar- coma, but it does not appear to span this region. None- lated primarily at the transcriptional level, in part by a theless, NFRKB may be particularly useful as the most positive regulatory region between nucleotides -299 and telomeric marker thus far assigned to 11q. © 1992 -243 (Lin et al., 1990) that contains the variant IL-2Ra Academic Press, Inc. KB site (Leung and Nabel, 1988). Despite the ability of IL-2Ra KB to bind NF-KB, functional assays can distin- guish the two related sites on the basis of their responses INTRODUCTION to phorbol esters and tumor necrosis factor a (TNF-a) (Leung and Nabel, 1988; Cross et al., 1989; Freimuth et Cellular proteins that bind specifically to cis-acting al., 1989; Adams et al., 1991). In addition, we have identi- regulatory sequences can modulate gene expression by fied a specific binding activity in nuclear extracts that enhancing or repressing transcriptional initiation. preferentially recognizes the IL-2Ra KB site (Adams et Highly conserved elements may be common to the regu- al., 1991). These results suggested that a protein distinct latory regions of several genes, and these elements may from NF-KB recognizes the KB-like sequence in the IL- participate in both coordinate regulation and differen- 2Ra enhancer. tial regulation of gene expression. One such conserved A cDNA encoding a nuclear factor that preferentially regulatory element is the 11-bp KB site found in the im- binds to the IL-2Ra KB site was isolated by probing a munoglobulin (Ig) light chain enhancer (Sen and Balti- hgtll expression library with radiolabeled multimerized more, 1986), human immunodeficiency viruses 1 and 2 IL-2Ra KB sites (Adams et aI., 1991). This factor, desig- (HIV-1, HIV-2) (Nabel and Baltimore, 1987; Markovitz nated RKB, is expressed preferentially in lymphoid cells et al., 1990), and several cellular and viral genes (Le- of T and B lineages in brain and in testis (Adams et al., nardo and Baltimore, 1989). Considerable structural 1991). RKB exhibits no similarity to previously cloned and functional heterogeneity of KB-binding proteins has KB-binding proteins and is unrelated to a known class of DNA-binding proteins. It is possible that RKB may play been demonstrated (Kieran et al., 1990; Ghosh et al., a role in directing tissue-specific expression through the 1990; Nolan et al., 1991; Baldwin et al., 1990; Fan and conserved KB element. These mapping studies were un- Maniatis, 1990; Perkins et al., 1992), including heteroge- dertaken to define the chromosomal location of the RKB neity in the components of NF-KB, the nuclear protein gene (HGM symbol NFRKB). complex that binds to the Ig/HIV KB site (Schmid et al., 1991). MATERIALS AND METHODS Isolation o[ human genomic RK13 clones. A human genomic HBP- To whom correspondence should be addressed. ALL library in Charon 30 (Rimm et al., 1980) (kindly provided by Dr. 270 0888-7543/92 $5.00 Copyright © 1992 by Academic Press, Inc. All rights of reproduction in any form reserved. ASSIGNMENT OF NFRKB TO 11q24-q25 271 Jeffrey Leiden) was screened at high stringency with a probe contain- concordance was found between human chromosome 11 ing RKB cDNA sequence from nucleotide 2703 to 2976 (EcoRl/SphI and the presence of RKB sequences (Table 1). fragment) (Adams et al., 1991) labeled with 82p by random hexamer- primed synthesis (Feinberg and Vogelstein, 1983). Three independent Chromosomal Localization of RKB by Fluorescence in positive clones were isolated from screening approximately 700,000 Situ Hybridization phage plaques. DNA from plaque-purified positive genomic clones was characterized by restriction mapping. EcoRI and BamHI fragments Further specification of RKB position on chromosome were subcloned into the Bluescript plasmid (Stratagene) for partial 11 was defined by FISH analysis using a 9.5-kb EcoRI sequencing. fragment from RKB genomic clone llA. Eighteen cells Isolation of human cosmid clones. Cosmid clones containing the were examined, in which fluorescence signals were ob- gene encoding RKB were isolated from an arrayed chromosome 11q- specific cosmid library that has been previously described (Evans and served on 49/72 chromatids. All 49 of the specific hybrid- Lewis, 1989). This library is archived as individual bacterial cultures ization signals localized to band llq24-q25 (Fig. 1). Cos- in 96-well microtiter plates. A 403-bp fragment from a human geno- mid clones 1Bll and 8H6 were also used for FISH analy- mic RKB clone, corresponding to cDNA sequences from nt 4470 to sis. Thirty metaphases were examined for each probe 4472, was labeled with z2p by random hexamer-primed synthesis and an FLpter location of 0.98 was determined. Compari- (Feinberg and Vogelstein, 1983) and hybridized to replicas of the arrayed clone libraries on nylon-based filter membranes. Cosmid son of the hybridization position with the visible band- clones 1Bll and 8H6 were identified as containing R~B coding se- ing pattern seen on some of the metaphases confirmed a quences by hybridization and by analysis with specific PCR primer band position of 1 lq24-q25. Two positions of hybridiza- sets derived from human RKB sequences from nt 4406 to 4435 (sense) tion were seen on each chromosome (one on each sister and from nt 4852 to 4881 (antisense). Additional characterization by chromatid) in >90% of metaphases examined. Southern blot analysis confirmed the identity of the clones. Somatic cell hybrids. DNA from the NIGMS Human Genetic Mu- Chromosomal Localization with Regard to the Ewing tant Cell Repository human/rodent somatic cell hybrid mapping Sarcoma (ES) Breakpoint panel No. 1 (Coriell Institute, Camden, NJ) was digested with EcoRI for Southern blot analysis with the 403-bp human RKB genomic probe To confirm the localization of RKB to chromosome described above. Hybridization was concordant with the presence of 11q24 and to determine the orientation relative to the human chromosome 11, although the highly conserved RKB sequences ES translocation breakpoint, an additional set of so- of the human probe also hybridized with rodent sequences. Chromo- matic cell hybrids was screened by PCR. Hybrid J1 (Kao somal location was subsequently confirmed in this panel and in a sec- ond somatic cell hybrid panel (previously described in Grissmer et al., et al., 1977) contains the entire chromosome 11. Cell 1990) by PCR analysis with the RKB-specific PCR primer set de- lines MC-1 and TG5DI-1 (Glaser et al., 1989; Evans and scribed above. The primers were derived from human RKB sequences Lewis, 1989) have been described previously (Glaser et corresponding to nt 4406 to 4435 (sense primer) and nt 4852 to 4881 al., 1989); these contain breakpoints in 11q23. Cell lines (antisense primer); PCR of rodent parent DNA with these primers was negative. Primer annealing and PCR extension phases were 66/23 and 66/36 are somatic cell hybrids constructed in carried out at 72°C. this laboratory (G. Hermanson and G. Evans, unpub- Fluorescence in situ hybridization (FISH). An EcoRI fragment of lished) that carry derivative chromosomes 11 and 22 iso- approximately 9.5 kb from RKB genomic clone lla was biotin-labeled lated from a Ewings sarcoma cell line. Cell line 66/23 by nick-translation (Bio-Nick Kit, BRL, Gaithersburg, MD) for use represents a somatic cell hybrid carrying the derll from as a probe in FISH. Metaphase chromosomes were prepared from pe- a ES cell line, representing the region from llpter to the ripheral blood lymphocytes by mitotic blockage. FISH was carried out as previously described (Pinkel et al., 1986) with DAPI counter- llq23-q24 ES breakpoint, isolated in a CHO back- staining. ground. Cell line 66/36 carries the der22, representing Cosmid clones 1Bll and 8H6 were utilized for fluorescence in situ the region from the 11q23-q24 ES breakpoint to llqter hybridization as previously described (Lichter et al., 1990; Selleri et from the same ES cell line isolated in a CHO back- al., 1991).
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