Sp1 is the majorfaslgene activator in abnormal CD4-CD8-B220+ T cells oflprandgldmice

Xiao, Sheng; Marshak‐Rothstein, Ann; Ju, Shyr‐Te

doi:10.1002/1521-4141(200111)31:11<3339::aid-immu3339>3.0.co;2-u

Cited by 10 publications

(7 citation statements)

References 51 publications

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“…Sp1-mediated processes include aberrant transcriptional modulation of dopamine receptor genes, neurodegeneration (2,13,14), and inflammatory processes (12,15), which are important in the pathogenesis of HD. However, various in vitro studies have implicated Sp1 as being prosurvival (16,17) or prodeath (18,19), or involved in neurodegeneration (10,14). Whereas interactions between Sp1 and mutant huntingtin appear to be deleterious at the molecular level (2), we have also demonstrated that blocking Sp1 using mithramycin A dramatically prolonged survival in a mouse model of HD (20).…”

Section: Huntington Disease (Hd)mentioning

confidence: 58%

Sp1 Is Up-regulated in Cellular and Transgenic Models of Huntington Disease, and Its Reduction Is Neuroprotective

Qiu

Norflus

Singh

et al. 2006

Journal of Biological Chemistry

101

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Interactions between mutant huntingtin (Htt) and a variety of transcription factors including specificity proteins (Sp) have been suggested as a central mechanism in Huntington disease (HD). However, the transcriptional activity induced by Htt in neurons that triggers neuronal death has yet to be fully elucidated. In the current study, we characterized the relationship of Sp1 to Htt protein aggregation and neuronal cell death. We found increased levels of Sp1 in neuronal-like PC12 cells expressing mutant Htt, primary striatal neurons, and brain tissue of HD transgenic mice. Sp1 levels were also elevated when 3-nitropropionate (3-NP) was used to induce cell death in PC12 cells. To assess the effects of knocking down Sp1 in HD pathology, we used Sp1 siRNA, a heterozygous Sp1 knock-out mouse, and mithramycin A, a DNA-intercalating agent that inhibits Sp1 function. The three approaches consistently yielded reduced levels of Sp1 which ameliorated toxicity caused by either mutant Htt or 3-NP. In addition, when HD mice were crossed with Sp1 heterozygous knock-out mice, the resulting offspring did not experience the loss of dopamine D2 receptor mRNA characteristic of HD mice, and survived longer than their HD counterparts. Our data suggest that enhancement of transcription factor Sp1 contributes to the pathology of HD and demonstrates that its suppression is beneficial. Huntington disease (HD)2 is a fatal hereditary neurodegenerative disorder characterized by progressive motor and cognitive deficits caused by neuronal dysfunction and degeneration affecting selected populations of neurons. The genetic defect responsible for HD is a CAG repeat expansion in exon 1 of the HD gene leading to the expression of a mutant huntingtin (Htt) protein containing an abnormally long polyglutamine sequence (1). Direct interactions between mutant Htt and a variety of transcription factors have been identified, which may significantly contribute to the pathogenesis of HD (2, 3). Gene microarray studies have indicated that selective transcriptional alterations occur early in HD (4), consistent with transcriptional dysregulation (5-7). Many of the altered genes contain binding sites for Sp1, which we recently demonstrated to interact with Htt in a polyglutamine lengthdependent manner (2).Sp1 is a zinc-finger domain (C terminus) transcriptional activator (8) that has been implicated in the expression of many genes in concert with other transcription factors, including the TAFII family (2), CREB (3, 9), nuclear factor-B (10), and vesicular endothelial growth factor receptor-2 (VEGFR-2) (11, 12). Sp1-mediated processes include aberrant transcriptional modulation of dopamine receptor genes, neurodegeneration (2, 13, 14), and inflammatory processes (12, 15), which are important in the pathogenesis of HD. However, various in vitro studies have implicated Sp1 as being prosurvival (16,17) or prodeath (18, 19), or involved in neurodegeneration (10,14). Whereas interactions between Sp1 and mutant huntingtin appear to be deleterious at the molecular l...

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Section: Huntington Disease (Hd)mentioning

confidence: 58%

Sp1 Is Up-regulated in Cellular and Transgenic Models of Huntington Disease, and Its Reduction Is Neuroprotective

Qiu

Norflus

Singh

et al. 2006

Journal of Biological Chemistry

101

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“…Lymphocytes prepared from gld lymph nodes were depleted of single positive T cells and B cells by treatment with a mixture of GK.1.5 anti-CD4 mAb, 53-6.7 anti-CD8 mAb and J11D anti-CD24 mAb at 37°C for 30 min, followed by the addition of rabbit complement (37). This treatment yields a viable cell population consisting of >90% abnormal DN T cells as assessed by¯ow cytometry.…”

Section: Enrichment Of the Abnormal Dn T Cells And Cd8 + T Cellsmentioning

confidence: 99%

Changes in sensitivity of peripheral lymphocytes of autoimmune gld mice to FasL-mediated apoptosis reveal a mechanism for the preferential deletion of CD4-CD8-B220+ T cells

Xiao

Zhang²,

Mann³

et al. 2004

International Immunology

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During thymic selection 'mis-selected' CD8(+) T cells exit to the periphery where they are deleted by a Fas/FasL-mediated mechanism, presumably as a result of activation by self-antigens. In the absence of functional FasL, as is the case in autoimmune gld mice, these 'mis-selected' T cells develop into unique Thy1(+)CD4(-)CD8(-) TCRalphabeta(+)B220(+) lymphocytes [abnormal double negative T (DN T) cells]. Using bioactive FasL-bearing vesicles [FasL vesicle preparation (FasL VP)], we were able to induce acute apoptosis in freshly isolated lymphocytes and to demonstrate that peripheral lymphocytes of gld mice become more sensitive to the FasL-mediated apoptosis as they age. Furthermore, flow cytometric analyses indicated that within this peripheral lymphocyte population, the abnormal DN T cells were preferentially eliminated. The exquisite sensitivity of these abnormal DN T cells is attributed to their increased membrane Fas expression with a concomitant reduction of cytosolic FLIP(L). Our data support the hypothesis that specific components of the Fas-mediated apoptotic pathway are modulated in favor of the elimination of auto-reactive T cells as well as those CD8(+) T cells that are 'mis-selected' in the thymus and escape to the periphery.

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“…The mRNA levels of Fas, FLIP, and ␤-actin were determined by RT-PCR as described (38,39). EMSA for activation-induced nuclear translocation of NF-B was carried out as described previously (39,40).…”

Section: Methodsmentioning

confidence: 99%

“…At various times after treatment, nuclear extracts were prepared. EMSA was conducted using the NF-B consensus probe (5Ј-CGCTTGATGAGT-CAGCCGGAA-3Ј, Promega, Madison, WI) and the Sp1 probe (5Ј-ATT-TCTGGGCGGATTCTTCCTGGG-3Ј) that we have described previously (39,41). The specificity of binding was determined by antibody-mediated supershift analysis using various anti-NF-B antibodies (39,40).…”

Section: Methodsmentioning

confidence: 99%

A Novel Signaling Mechanism for Soluble CD95 Ligand

Xiao

Jodo

Sung

et al. 2002

Journal of Biological Chemistry

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Sp1 is the majorfaslgene activator in abnormal CD4-CD8-B220+ T cells oflprandgldmice

Cited by 10 publications

References 51 publications

Sp1 Is Up-regulated in Cellular and Transgenic Models of Huntington Disease, and Its Reduction Is Neuroprotective

Sp1 Is Up-regulated in Cellular and Transgenic Models of Huntington Disease, and Its Reduction Is Neuroprotective

Changes in sensitivity of peripheral lymphocytes of autoimmune gld mice to FasL-mediated apoptosis reveal a mechanism for the preferential deletion of CD4-CD8-B220+ T cells

A Novel Signaling Mechanism for Soluble CD95 Ligand

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