The Role of B-Cell-Specific Activator Protein in the Response of Malignant B-1 Cells to LPS

Zhang, Ming; Chong, Siew Yen; Raveché, Elizabeth

doi:10.1006/excr.2000.5122

Cited by 3 publications

(2 citation statements)

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“…Other groups have also demonstrated the role of BSAP in regulating apoptosis [ 36 ]. Previously, we demonstrated that inhibition of BSAP lead to decreased proliferation and apoptosis in malignant B-1 cells from the NZB murine model of CLL [ 37 ] [ 38 ] [ 39 ]. In the present study we have shown that knocking down BSAP leads to malignant cell death not only in our murine CLL cell line but also in ex vivo patient PBMC via upregulation of miR15a/16 levels.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic implications of activation of the host gene (Dleu2) promoter for miR-15a/16-1 in chronic lymphocytic leukemia

et al. 2013

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Genetic lesions and other regulatory events lead to silencing of the 13q14 locus in a majority of chronic lymphocytic leukemia (CLL) patients. This locus encodes a pair of critical pro-apoptotic microRNAs, miR-15a/16-1. Decreased levels of miR-15a/16-1 are critical for the increased survival exhibited by CLL cells. Similarly, in a de novo murine model of CLL, the NZB strain, germline-encoded regulation of the syntenic region resulted in decreased miR-15a/16-1. In this paper we have identified additional molecular mechanisms regulating miR-15a/16-1 levels and shown that the transcription factor BSAP (B cell Specific Activator Protein) directly interacts with Dleu2, the host gene containing the mir-15a/16-1 loci and via negative regulation of the Dleu2 promoter results in repression of mir-15a/16 expression. CLL patient B cell expression levels of BSAP were increased compared to control sources of B cells. With the use of siRNA mediated repression, the levels of BSAP were decreased in vitro in the NZB derived malignant B1 cell line, LNC, and in ex vivo CLL patient PBMC. BSAP knockdown led to an increase in the expression of miR-15a/16-1 and an increase in apoptosis and a cell cycle arrest in both the cell line and patient PBMC. Moreover, using Dleu2 promoter analysis by chromatin immunoprecipitation (ChIP) assay we have shown that BSAP directly interacts with the Dleu2 promoter. Derepression of the Dleu2 promoter via inhibition of histone deacetylation combined with BSAP knockdown increased miR-15a/16 expression and increased malignant B cell death. In summary, therapy targeting enhanced host gene Dleu2 transcription may augment CLL therapy.

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Section: Discussionmentioning

confidence: 99%

Therapeutic implications of activation of the host gene (Dleu2) promoter for miR-15a/16-1 in chronic lymphocytic leukemia

et al. 2013

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“…Another study reported a time‐dependent decrease in the levels of Pax5 mRNA, protein and DNA binding activity in LPS‐activated CH12.LX cells, demonstrating the functional role of Pax5 as a repressor of B‐cell differentiation [Yoo et al, 2004]. It has been also reported that LPS induced the Pax5 DNA binding activity in malignant B‐1 cells during the initial activation stage (24 h), while prolonged LPS treatment (72 h) resulted in a subsequent decrease in Pax5 levels, and these events correlated with an initial augmentation in proliferation followed by apoptosis and pathological differentiation [Zhang et al, 2001]. Increased 1‐cysPrx expression was reported in actively proliferating corneal tissues during wound healing process after photorefractive keratectomy, and in proliferating bovine keratocytes as the result of growth factor treatment, suggesting 1‐cysPrx involvement in cell proliferation [Tchah et al, 2005].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional regulation of the murine 1‐cys peroxiredoxin gene by the B cell‐specific activator protein, Pax5

Lee

Choi

Kim

et al. 2008

J of Cellular Biochemistry

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Pax5, a member of the paired box gene family of transcription factors, is a B cell-specific activator protein (BSAP) that plays important roles in controlling the expression of lineage- and differentiation-stage specific genes during B lymphopoiesis. We identified two putative Pax5 binding sites in a 668 bp of the murine 1-cys peroxiredoxin (1-cysPrx) promoter region. These sites were located at positions -278 to -262 and -50 to -34 from the translation start site. Gel mobility shift assays showed that recombinant Pax5 protein bound specifically to the nucleotide regions -56 to -24 (MP1 probe) and -284 to -253 (MP2 probe). Furthermore, endogenous Pax5 protein from B lymphoblast cells (IM-9) formed a DNA-protein complex with MP1 and MP2 probes, indicating that Pax5 binding occurs specifically at these sequences in vivo. Transient transfection studies showed that expression of exogenous Pax5 resulted in dose-dependent increases in 1-cysPrx promoter activity, implying that Pax5 functions as a positive transcription factor for 1-cysPrx expression. Further transient cotransfection studies showed that coexpression of Pax5 and histone acetyltransferases (HATs), such as p300, cAMP-response-element-binding protein (CBP) and p300/CBP associated factor (PCAF) enhanced the Pax5-mediated 1-cysPrx promoter activity. Immunoprecipitation studies indicated that Pax5 directly binds to HATs. Chromatin immunoprecipitation assays showed that the recruitment of Pax5 to the promoter induced histone H3 and H4 hyperacetylation of chromatin. Lipopolysaccharides (LPS) stimulation of murine splenocytes resulted in coordinated expression of Pax5 and 1-cysPrx proteins. These findings suggest that Pax5 may function as a transactivator of 1-cysPrx gene expression.

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SC3 monoclonal antibody defines a novel specific human B-cell surface antigen differentially expressed on B-cell leukaemias and lymphomas and involved in the proliferation of normal and malignant B lymphocytes

Nikolova

Guenova

Taskov

et al. 2005

Cellular Immunology

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The Role of B-Cell-Specific Activator Protein in the Response of Malignant B-1 Cells to LPS

Cited by 3 publications

References 50 publications

Therapeutic implications of activation of the host gene (Dleu2) promoter for miR-15a/16-1 in chronic lymphocytic leukemia

Therapeutic implications of activation of the host gene (Dleu2) promoter for miR-15a/16-1 in chronic lymphocytic leukemia

Transcriptional regulation of the murine 1‐cys peroxiredoxin gene by the B cell‐specific activator protein, Pax5

SC3 monoclonal antibody defines a novel specific human B-cell surface antigen differentially expressed on B-cell leukaemias and lymphomas and involved in the proliferation of normal and malignant B lymphocytes

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