Combinatorial regulation of the murine RAG-2 promoter by Sp1 and distinct lymphocyte-specific transcription factors

Miranda, Gustavo A.; Villalvazo, Maria; Galić, Zoran; Alva, Jackelyn A.; Abrines, Roxanna; Yates, Yvette; Evans, Cory J.; Aguilera, Renato J.

doi:10.1016/s0161-5890(02)00007-x

Cited by 19 publications

(11 citation statements)

References 49 publications

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“…A very similar activation profile was observed using reporters driven by established Myb-responsive promoters (Figures 6b and c), both the murine RAG-2 promoter (Wang et al, 2000;Miranda et al, 2002) and the MYC promoter (Schmidt et al, 2000). Here the FLASH-induced enhancement was three to fourfold the level measured with c-Myb alone.…”

Section: Flash Enhances C-myb-dependent Reporter Activationsupporting

confidence: 78%

FLASH acts as a co-activator of the transcription factor c-Myb and localizes to active RNA polymerase II foci

et al. 2008

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The c-Myb oncoprotein is a DNA-binding transcription factor with a key role in early stages of hematopoiesis. To expand our knowledge of partners cooperating with c-Myb, we performed a yeast two-hybrid screening with full-length c-Myb as bait. Here, we report FLICEassociated huge protein (FLASH)/CASP8AP2 as a novel Myb-interacting protein. We show that FLASH interacts with the DNA-binding domain of c-Myb and enhances c-Myb-dependent reporter activity and expression of endogenous c-Myb target genes. Chromatin immunoprecipitation assays revealed that FLASH and c-Myb both associate with the MYC promoter region as well as with the intronic enhancer of the c-Myb target gene ADA. Furthermore, siRNA knock-down of FLASH or c-Myb both result in a reduction of MYC and ADA expression. The co-activator effect is mediated through the C-terminal part of FLASH, which binds c-Myb. The FLASH-induced enhancement is comparable with the increase seen with the c-Myb co-activator p300. We find FLASH localized in discrete nuclear speckles in several cell lines, co-localized with c-Myb in active RNA polymerase II foci. These results imply a novel molecular mechanism of regulation of c-Myb activity. We propose that c-Myb cooperates with FLASH in foci associated with active RNA polymerase II, leading to enhancement of Myb-dependent gene activation.

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Section: Flash Enhances C-myb-dependent Reporter Activationsupporting

confidence: 78%

FLASH acts as a co-activator of the transcription factor c-Myb and localizes to active RNA polymerase II foci

et al. 2008

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“…As demonstrated by experiments with transgenic mice, the expression of rag genes is tightly regulated: in addition to the rag1 and rag2 promoters [Fuller and Storb, 1997;Miranda et al, 2002], two regulatory regions considered enhancers or part of a locus-control region (LCR), have been identified, both on the rag2 side of the locus [Yu et al, 1999;Hsu et al, 2003]. Moreover, Yannoutsos et al [2004] reported on an element, in the rag locus, functioning as an antisilencer element that counteracts a silencer located in the intergenic region between rag1 and rag2.…”

Section: Cd8mentioning

confidence: 99%

RAG-dependent primary immunodeficiencies

et al. 2006

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Mutations in recombination activating genes 1 and 2 (RAG1 and RAG2) cause a spectrum of severe immunodeficiencies ranging from classical T cell-B cell-severe combined immunodeficiency (T(-)B(-)SCID) and Omenn syndrome (OS) to an increasing number of peculiar cases. While it is well established from biochemical data that the specific genetic defect in either of the RAG genes is the first determinant of the clinical presentation, there is also increasing evidence that environmental factors play an important role and can lead to a different phenotypic expression of a given genotype. However, a better understanding of the mechanisms by which the molecular defect impinges on the cellular phenotype of OS is still lacking. Ongoing studies in knock-in mice could better clarify this aspect.

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“…4 PAX5-binding sites have been identified in the regulatory sequences of a number of genes, including CD19, 5 BLK, 6 BLNK, 7 MB1 (Ig␣), N-myc, LEF1, 8 and RAG2. 9 PAX5 can act as an activator or a repressor of transcription. It has been shown to activate CD19, N-myc, MB1, and LEF1 expression and to repress PD-1 transcription.…”

Section: Introductionmentioning

confidence: 99%

A novel PAX5-ELN fusion protein identified in B-cell acute lymphoblastic leukemia acts as a dominant negative on wild-type PAX5

Bousquet

Broccardo

Quelen

et al. 2006

Blood

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We report a novel t(7;9)(q11;p13) translocation in 2 patients with B-cell acute lymphoblastic leukemia (B-ALL). By fluorescent in situ hybridization and 3 rapid amplification of cDNA ends, we showed that the paired box domain of PAX5 was fused with the elastin ( IntroductionPAX5 is a member of the highly conserved paired-box (PAX) domain family of transcription factors. The PAX5 gene plays an important role in both cell differentiation as well as in embryonic development, and is located on chromosome 9p13. 1 This locus contains 2 distinct promoters, resulting in 2 alternative 5Ј exons (1a and 1b). 2 PAX5b is transcribed in the central nervous system and testis as well as in the B-lymphoid lineage, while PAX5a, also named B-cell-specific activator protein (BSAP), is specifically transcribed in the lymphoid lineage. PAX5a/BSAP is expressed from early stages of B-cell development up to mature B cells and is down-regulated during terminal differentiation into plasma cells. 3 In bone marrow of Pax5 Ϫ/Ϫ mice, B lymphopoiesis is completely arrested at the pro-B stage, revealing the essential role of this gene in early B-cell lymphopoiesis. 4 PAX5-binding sites have been identified in the regulatory sequences of a number of genes, including CD19, 5 BLK, 6 BLNK, 7 MB1 (Ig␣), N-myc, LEF1, 8 and RAG2. 9 PAX5 can act as an activator or a repressor of transcription. It has been shown to activate CD19, N-myc, MB1, and LEF1 expression and to repress PD-1 transcription. 8 PAX5 plays an essential role in B-cell lineage commitment by suppressing alternative lineage choices. [10][11][12] Indeed, it represses the transcription of Notch1, which is necessary for the commitment of lymphoid progenitors to the T-cell pathway, 13 and the transcription of M-CSFR, thus rendering B-cell precursors unresponsive to the myeloid cytokines such as macrophage colony-stimulating factor (M-CSF). 12 Chromosomal translocations involving the PAX5 gene have been described in different types of B-cell malignancies. The t(9;14)(p13;q32) translocation in B-cell non-Hodgkin lymphoma results in juxtaposition of the complete coding sequence of PAX5 to the IGH gene cluster, and leads to elevated PAX5 expression. 14,15 Moreover, PAX5 is involved in the chimeric transcript PAX5-ETV6 in patients with B-cell acute lymphoblastic leukemia (B-ALL) who have a dic(9;12)(p13;p13) translocation. 16,17 The latter fusion protein retains the paired-box domain of PAX5 fused to the helix-loop-helix and DNA-binding domain of ETV6. In this case, the chimeric protein most probably acts as an aberrant transcription factor. 17 The paired box is a DNA-binding domain that is highly conserved during evolution in all PAX genes. [18][19][20] This domain is conserved in all fusion transcripts involving a PAX gene, including PAX5-ETV6 and others described, such as PAX3-FKHR 21 and PAX8-PPARG1. 22 PAX5 also contains a conserved octapeptide motif and a partial homeodomain. The C-terminal region contains a transcriptional activation domain, and the extreme C-terminal region acts as a repr...

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Combinatorial regulation of the murine RAG-2 promoter by Sp1 and distinct lymphocyte-specific transcription factors

Cited by 19 publications

References 49 publications

FLASH acts as a co-activator of the transcription factor c-Myb and localizes to active RNA polymerase II foci

FLASH acts as a co-activator of the transcription factor c-Myb and localizes to active RNA polymerase II foci

RAG-dependent primary immunodeficiencies

A novel PAX5-ELN fusion protein identified in B-cell acute lymphoblastic leukemia acts as a dominant negative on wild-type PAX5

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