Transcription of the blk Gene in Human B Lymphocytes Is Controlled by Two Promoters

Lin, Yu-Huei; Shin, Edward J.; Campbell, Michael J.; Niederhuber, John E.

doi:10.1074/jbc.270.43.25968

Cited by 34 publications

(17 citation statements)

References 56 publications

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“…In these experiments potential Z-DNA-forming sequences have been either deleted from or introduced into reporter plasmids, and inhibitory or enhancing effects were observed (24)(25)(26). The contribution of the potential Z-DNA-forming sequences to the observed effects is probable, but adjacent sequences also may play a role.…”

Section: Discussionmentioning

confidence: 99%

A polymorphic dinucleotide repeat in the rat nucleolin gene forms Z-DNA and inhibits promoter activity

Rothenburg

Koch-Nolte

Rich

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

131

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Many sequences in eukaryotic genomes have the potential to adopt a left-handed Z-DNA conformation. We used a previously described assay based on the binding of a mAb to Z-DNA to inquire whether Z-DNA is formed in the rat nucleolin (Ncl) gene in metabolically active, permeabilized nuclei. Using real-time PCR to measure Z-DNA formation, the potential Z-DNA sequence element Z1 [(CA) 10(CG)8] in the promoter region was found to be enriched 571-to 4,040-fold in different cell lines, whereas Z2 [AC(GC) 5CCGT(CG)2] in the first intron was enriched 12-to 34-fold. Ncl promoter activity was 1.5-to 16-fold stronger than that of the simian virus 40 promoter and enhancer. This activity was further increased 36 -54% when Z1 was deleted. The inhibitory effect of Z1 on Ncl promoter activity was independent of location and orientation. The Ncl Z1 element is identical to the genetic marker D9Arb5. Five allelic variants of Z1 were identified by sequence analysis of genomic DNA from various rats. The two most common alleles differed significantly (up to 27%) in their capacity to inhibit Ncl promoter activity. This finding suggests that differences in Z-DNA formation by polymorphic dinucleotide repeats may be one of the factors contributing to genetic variation.gene regulation ͉ polymorphism ͉ microsatellites ͉ left-handed DNA D inucleotide repeats are found throughout the genome of eukaryotes. (CA͞TG) n is the most abundant one in mammals, found on average every 20-30 kb (1). These microsatellites often are polymorphic and have been used extensively in genetic mapping and the identification of susceptibility loci in genetic diseases (2). Evidence is accumulating that such elements also can be of functional importance. Dinucleotide repeats have the potential to form alternative DNA structures such as Z-DNA, H-DNA, and cruciform DNA (3, 4). One of the bestcharacterized alternative DNA conformations is left-handed Z-DNA, which can be adopted by stretches of alternating purine-pyrimidine nucleotides.Z-DNA formation of many sequences can be induced in vitro (5). (CG) n repeats have the highest potential to form Z-DNA, followed by (CA͞TG) n and (TA) n (5). Sequences containing alternating purine-pyrimidine nucleotides have been shown to modulate promoter activity. They may either enhance (6, 7) or repress (8) promoter activity. Because of the polymorphic nature of dinucleotide repeats, it seems possible that Z-DNA-forming sequences may provide a source of genetic variation if they occur in regions that are important for the regulation of gene activity.An assay based on the preparation of metabolically active nuclei, introduced by Jackson and Cook (9), has been developed to investigate whether specific potential Z-DNA-forming sequences actually adopt this conformation in actively transcribing eukaryotic genes (10). These nuclei maintain transcription and show a DNA replication rate of 85%, compared with untreated cells (11). The permeable nuclei are incubated with a biotinylated mAb specific for Z-DNA. A 10-ns laser pulse at 266 nm is use...

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Section: Discussionmentioning

confidence: 99%

A polymorphic dinucleotide repeat in the rat nucleolin gene forms Z-DNA and inhibits promoter activity

Rothenburg

Koch-Nolte

Rich

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

131

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“…Indeed, it has previously been reported that Jurkat cells express low levels of Blk mRNA. 22,39 However, protein expression of Blk was not observed in the Jurkat cells ( Figure 1C). Confirming the identity of the band recognized as Blk, transfection of the malignant CTCL cell lines with Blkspecific siRNA induced a selective down-regulation of the band, whereas the expression of Erk remained unaffected ( Figure 1D; data not shown).…”

Section: Selective Expression Of Blk In Malignant Ctcl Cell Linesmentioning

confidence: 99%

“…39,41,42 CTCL cell lines expressed both of the NF-B subunits, p65 and p50, with the latter being overexpressed, compared with nonmalignant T-cell lines ( Figure S1). In contrast, no expression of Pax-5 mRNA was detected (data not shown), suggesting that NF-B is a candidate transcription factor in CTCL.…”

Section: Expression Of Blk Is Induced By Nf-bmentioning

confidence: 99%

Ectopic expression of B-lymphoid kinase in cutaneous T-cell lymphoma

Krejsgaard

Vetter-Kauczok

Woetmann

et al. 2009

Blood

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IntroductionCutaneous T-cell lymphomas (CTCL) are the most frequent primary lymphomas of the skin, with mycosis fungoides (MF) being the most prevalent clinical form. 1 In early disease stages, which can last several years, MF presents as flat erythematous skin patches resembling inflammatory diseases such as allergic contact dermatitis, eczema, or psoriasis. In later stages, MF lesions gradually form plaques and overt tumors and may disseminate to lymph nodes and internal organs. The early skin lesions contain numerous inflammatory cells, including a large quantity of T cells with a normal phenotype as well as a small population of T cells with abnormal morphology and a malignant phenotype. T cells with a malignant phenotype are characterized by epidermotropism and are preferentially present in the upper parts of the skin, whereas T cells with a normal phenotype primarily are detected in the lower portions of the dermis. The epidermal T cells are sometimes found in patterns of Pautrier microabscesses, which are collections of T cells adherent to dendritic processes of Langerhans cells. During disease development, the epidermotropism is gradually lost concomitant with an increase in malignant, and a decrease in nonmalignant, infiltrating T cells. The etiology of CTCL remains poorly understood, and occupational exposures, infectious agents, and genetic mutations have been proposed as etiological factors, but no evidence of causation has been provided. [2][3][4][5][6] However, already in early disease stages, the transcription factor nuclear factor-kappa B (NF-B) has been shown to be constitutively active in the malignant T cells of patients with CTCL where it promotes proliferation and cell survival. [7][8][9] The malignant T cells also show aberrant hyperactivation of the Janus kinase 3 (Jak3)/signal transducer and activator of transcription 3 (Stat3) pathway, which protects them from apoptosis and is a marker of resistance to therapy. [10][11][12][13] It has been hypothesized that the aberrant activation of NF-B and the Jak3/Stat3 pathway are key events in the development of CTCL. [7][8][9][10] Early diagnosis of CTCL has important consequences concerning therapeutic options and determination of prognosis. 14 Currently, it is primarily based on clinical observations and histologic examinations of cutaneous biopsies as well as additional laboratory tests such as analysis of T-cell receptor (TCR) clonality by polymerase chain reaction (PCR). Unfortunately, early diagnosis of CTCL has proven difficult because of the great clinical, pathologic, and histologic resemblance to benign inflammatory skin diseases and because inflammatory skin disorders can be associated with clonal TCR rearrangements. [15][16][17][18] In humans, the Src family kinases (SFKs) of nonreceptor protein tyrosine kinases classically consists of 8 members: c-Src, Fyn, Lck, c-Yes, Fgr, Hck, Lyn, and B-lymphoid kinase (Blk). 19 Blk is exclusively expressed in B cells and thymocytes but not in mature T cells. [20][21][22] Besides a role of Blk in B...

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“…3D and data not shown). We examined 10 downstream target genes (seven positively regulated direct target genes and three negatively regulated genes) of PAX5 (10)(11)(12) and found that four, including ATP1B1, BLK, NEDD5 and TCF7L2, were down-regulated by induction of either PAX5-C20orf112S or PAX5-C20orf112L protein. However, expression of other reported PAX5 downstream target genes, including three positively regulated direct target genes (IRF8, BST1, CD19) and three negatively regulated genes (CCR2, CCR5, NOTCH1) were not affected by the induction of expression of the fusion proteins in these cells.…”

Section: Genes Involved In Unbalanced Translocationsmentioning

confidence: 99%

Cloning of genes involved in chromosomal translocations by high-resolution single nucleotide polymorphism genomic microarray

Kawamata

Ogawa

Zimmermann

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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High-resolution single nucleotide polymorphism genomic microarray (SNP-chip) is a useful tool to define gene dosage levels over the whole genome, allowing precise detection of deletions and duplications/amplifications of chromosomes in cancer cells. We found that this new technology can also identify breakpoints of chromosomes involved in unbalanced translocations, leading to identification of fusion genes. Using this technique, we found that the PAX5 gene was rearranged to a variety of partner genes including ETV6, FOXP1, AUTS2, and C20orf112 in pediatric acute lymphoblastic leukemia (ALL). The 3 end of the PAX5 gene was replaced by the partner gene. The PAX5 fusion products bound to PAX5 recognition sequences as strongly as wild-type PAX5 and suppressed its transcriptional activity in a dominant-negative fashion.

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Transcription of the blk Gene in Human B Lymphocytes Is Controlled by Two Promoters

Cited by 34 publications

References 56 publications

A polymorphic dinucleotide repeat in the rat nucleolin gene forms Z-DNA and inhibits promoter activity

A polymorphic dinucleotide repeat in the rat nucleolin gene forms Z-DNA and inhibits promoter activity

Ectopic expression of B-lymphoid kinase in cutaneous T-cell lymphoma

Cloning of genes involved in chromosomal translocations by high-resolution single nucleotide polymorphism genomic microarray

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