Sp1 and Sp3 Are Oxidative Stress-Inducible, Antideath Transcription Factors in Cortical Neurons

Ryu, Hoon; Lee, Jung‐Hee; Zaman, Khalequz; Kubilis, James; Ferrante, Robert J.; Ross, Brian D.; Neve, Rachael; Ratan, Rajiv R.

doi:10.1523/jneurosci.23-09-03597.2003

Cited by 214 publications

(189 citation statements)

References 61 publications

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“…Sp-1 modulates gene transcription of tissue plasminogen activator which depends on the retinoic acid and cAMP. A protective role of Sp-1 was found during oxidative stress in brain neurons [9,14]. The regulation of gene expression by Egr-1 and Sp-1 transcription factors showed an interaction between them, since DNA-binding domains of these factors overlap [14,17].…”

Section: Resultsmentioning

confidence: 99%

The disturbance of oxidant-antioxidant balance in rat colonic mucosa after antibiotic therapy

Holota¹,

Tjapko²,

Dovbynchuk³

et al. 2015

Biol. Stud.

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Antibiotic treatment increases susceptibility to development of inflammatory bowel diseases (IBD) both in children and adults. Oxidative stress plays a prominent role in IBD pathogenesis. The aim of present study was to test an interrelationship between the morphological changes in rat colonic mucosa, the levels of antioxidant enzymes and redox sensitive transcription factors Egr-1 and Sp-1 after treatment with cephalosporin antibiotic ceftriaxone (Cf) with broad spectrum of action. Study was performed on male Wistar rats (180-230 g). Cf (50 mg/kg, i.m.) were injected daily for 5 days. The colonic levels of catalase and superoxide dismutase activity were measured by the colorimetric assays and zymography; levels of Egr-1 and Sp-1 -by Western-blot analysis; histological chan ges -by morphometric analysis. Body weight and diarrhea were recorded. Systemic administration of the ceftriaxone induced morphological and functional changes in rat colonic mucosa associated with initial stages of the acute inflammation. These changes were accompanied by a decrease of activity of superoxide dismutase and catalase. Levels of redox-sensitive transcription factors Egr-1 and Sp1 were significantly increased, which shows a disturbance of homeostasis of the intestinal barrier.

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Section: Resultsmentioning

confidence: 99%

The disturbance of oxidant-antioxidant balance in rat colonic mucosa after antibiotic therapy

Holota¹,

Tjapko²,

Dovbynchuk³

et al. 2015

Biol. Stud.

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“…These results suggest that Sp1 is required for cell survival and/or proliferation (Marin et al, 1997). Accordingly, sustained expression of Sp1 protects primary cortical neurons from cell death induced by oxidative stress or DNA damage (Ryu et al, 2003b). In the same cells, acetylation of Sp1 has recently been associated with increased Sp1-dependent transcription and resistance of neurons to oxidative stressinduced death in vitro and in vivo (Ryu et al, 2003a).…”

Section: Introductionmentioning

confidence: 91%

Overexpression of Sp1 transcription factor induces apoptosis

et al. 2006

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Transcription factor Sp1 has recently been shown to be overexpressed in a number of human cancers and its overexpression contributes to malignant transformation. Sp1 regulates the expression of a number of genes participating in multiple aspects of tumorigenesis such as angiogenesis, cell growth and apoptosis resistance. To better understand the role of increased Sp1 levels on apoptosis regulation we have used retroviruses to overexpress this protein in haematopoietic Baf-3 cells and in 3T3 fibroblasts. We have also used inducible expression systems to control ectopic Sp1 levels in different cell types. Surprisingly, Sp1 overexpression on its own induces apoptosis in all the cellular models tested. The apoptotic pathways induced by Sp1 overexpression are cell type specific. Finally, using a truncated form of Sp1, we show that Sp1-induced apoptosis requires its DNA-binding domain. Our results highlight that Sp1 levels in untransformed cells must be tightly regulated as Sp1 overexpression leads to the induction of apoptosis. Our results also suggest that cancer cells overexpressing Sp1 can avoid Sp1-induced apoptosis.

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“…The SH-SY5Y cells were used in the transient transfection assays and were treated with mithramycin at 10 or 50 M for the indicated times. Reporter activity assays (at 48 h after transfection) and data analysis were performed (39). …”

Section: Acid Extraction Of Histone Protein and Histone Methylation Amentioning

confidence: 99%

ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease

Ryu

Lee

Hagerty

et al. 2006

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

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284

250

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Chromatin remodeling and transcription regulation are tightly controlled under physiological conditions. It has been suggested that altered chromatin modulation and transcription dysfunction may play a role in the pathogenesis of Huntington's disease (HD). Increased histone methylation, a well established mechanism of gene silencing, results in transcriptional repression. ERG-associated protein with SET domain (ESET), a histone H3 (K9) methyltransferase, mediates histone methylation. We show that ESET expression is markedly increased in HD patients and in transgenic R6/2 HD mice. Similarly, the protein level of trimethylated histone H3 (K9) was also elevated in HD patients and in R6/2 mice. We further demonstrate that both specificity protein 1 (Sp1) and specificity protein 3 (Sp3) act as transcriptional activators of the ESET promoter in neurons and that mithramycin, a clinically approved guanosine-cytosine-rich DNA binding antitumor antibiotic, interferes with the DNA binding of these Sp family transcription factors, suppressing basal ESET promoter activity in a dose dependent manner. The combined pharmacological treatment with mithramycin and cystamine down-regulates ESET gene expression and reduces hypertrimethylation of histone H3 (K9). This polytherapy significantly ameliorated the behavioral and neuropathological phenotype in the R6/2 mice and extended survival over 40%, well beyond any existing reported treatment in HD mice. Our data suggest that modulation of gene silencing mechanisms, through regulation of the ESET gene is important to neuronal survival and, as such, may be a promising treatment in HD patients. H untington's disease (HD) is an autosomal-dominant inherited neurological disorder caused by expanded stretches of CAG repeats coding for glutamine in the Huntingtin (Htt) gene. Polyglutamine [poly(Q)] expansions of mutant Htt (mtHtt) protein lead to a number of cellular abnormalities that include altered nucleosome dynamics and subsequent transcriptional dysregulation (1-4). Consistent with transcriptional repression playing a role in the pathogenesis of HD, decreased acetylation and increased methylation of histones, well established mechanisms of gene activation and silencing, have been found in HD experimental models (5-8). Histone acetylation is involved in the regulation of gene expression and is regulated by the opposing activities of histone acetyltransferases and histone deacetylases (HDACs) (9). The poly(Q) stretches in mtHtt interact physically with CREB binding protein (CBP), a transcriptional coactivator, and block intrinsic CBP histone acetyltransferase activity (2, 5). These specific interactions have led to a model in which mtHtt, by harboring extra glutamines, becomes a hyperactive glutamine-containing corepressor (10). Transcriptional repression may also be attributable to epigenetic modifications, such as histone methylation and histone deacetylation (11). Thus, transcriptional dysfunction has been proposed to play an important role in the neuronal cell death of HD and has be...

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Sp1 and Sp3 Are Oxidative Stress-Inducible, Antideath Transcription Factors in Cortical Neurons

Cited by 214 publications

References 61 publications

The disturbance of oxidant-antioxidant balance in rat colonic mucosa after antibiotic therapy

The disturbance of oxidant-antioxidant balance in rat colonic mucosa after antibiotic therapy

Overexpression of Sp1 transcription factor induces apoptosis

ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Huntington's disease

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