Transcriptional regulation of the cystathionine-β-synthase gene in Down syndrome and non–Down syndrome megakaryocytic leukemia cell lines

Ge, Yubin; Jensen, Tanya L.; Matherly, Larry H.; Taub, Jeffrey W.

doi:10.1182/blood-2002-07-2337

Cited by 45 publications

(30 citation statements)

References 20 publications

(37 reference statements)

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“…Changes in SP1 phosphorylation result in either facilitation or suppression of DNA binding, promoter activation [31][32][33] and gene transcription [34][35][36]. SP1 protein can be phosphorylated at various sites by different kinases including protein kinase A, protein kinase C, MAPK, casein kinases 1 and 2, and calmodulin kinases [37].…”

Section: Discussionmentioning

confidence: 99%

Rat pancreatic level of cystathionine γ-lyase is regulated by glucose level via specificity protein 1 (SP1) phosphorylation

et al. 2011

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Aims/hypothesis Cystathionine γ-lyase (CSE) catalyses the endogenous production of hydrogen sulphide (H 2 S) in pancreatic beta cells, and H 2 S has been shown to inhibit insulin release from these cells. As altered pancreatic H 2 S production modulated by glucose has been previously shown, we hypothesised that the Cse gene could be regulated by glucose level in insulin-secreting cells. Methods The effects of glucose on CSE protein level and mRNA level were analysed in INS-1E cells. Glucose effect on Cse promoter activity was tested by constructing a proximal Cse promoter vector including specificity protein 1 (Sp1) consensus sequence. Results High glucose (20 mmol/l) inhibited H 2 S production in INS-1E cells and freshly isolated rat pancreatic islets. Cse mRNA expression, CSE activity and protein abundance were also profoundly reduced by high glucose. The involvement of SP1 in basal and high-glucose-regulated CSE production was demonstrated. Sp1-knockdown abolished a large portion of CSE production at basal glucose. Phosphorylation of SP1 stimulated by high glucose was inhibited by p38 mitogenactivated protein kinase (MAPK) inhibitors SB203580 and SB202190. After blocking p38 MAPK phosphorylation, the inhibitive effects of high glucose on CSE protein production and promoter activity in INS-1E cells were also virtually abolished. Conclusions/interpretation Glucose stimulates the phosphorylation of SP1 via p38 MAPK activation, which leads to decreased Cse promoter activity and subsequent downregulation of Cse gene expression. Inhibited H 2 S production through glucosemediated CSE activity and production alterations may be involved in the fine control of glucose-induced insulin secretion.

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Section: Discussionmentioning

confidence: 99%

Rat pancreatic level of cystathionine γ-lyase is regulated by glucose level via specificity protein 1 (SP1) phosphorylation

et al. 2011

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“…The DS AMkL cell line, CMK, and the non-DS AMkL cell line, CMS, were cultured as described previously (22). THP-1, HL60, and U937 leukemia cell lines and the human HT1080 fibrosarcoma cell line were obtained from the American Type Culture Collection (Manassas, VA) and maintained in RPMI 1640 containing 10% heat-inactivated calf serum (Hyclone Labs, Logan, UT), 100 units/ml penicillin, and 100 g/ml streptomycin in a humidified atmosphere at 37°C in the presence of 5% CO 2 /95% air.…”

Section: Methodsmentioning

confidence: 99%

“…In vitro cytotoxicities of DS and non-DS leukemia cell lines were determined as described previously (22). The IC 50 s were calculated as the concentration of drug necessary to inhibit 50% growth compared with control cells cultured in the absence of drug.…”

Section: Methodsmentioning

confidence: 99%

The Role of Cytidine Deaminase and GATA1 Mutations in the Increased Cytosine Arabinoside Sensitivity of Down Syndrome Myeloblasts and Leukemia Cell Lines

Jensen

Stout

et al. 2004

Cancer Research

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“…Subsequent reports regarding the CBS basal promoter activity have been essentially confined to this 481-bp region (12,13,19). However, it is not unusual for sequence elements several kbp upstream of the transcriptional start sites to contain sequence elements that significantly modulate basal activity or confer tissue-specific expression.…”

Section: Defining the Cbs ϫ1bmentioning

confidence: 99%

The Dominant Role of Sp1 in Regulating the Cystathionine β-Synthase –1a and –1b Promoters Facilitates Potential Tissue-specific Regulation by Kruppel-like Factors

Maclean

Kraus

2004

Journal of Biological Chemistry

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Cystathionine ␤-synthase (CBS) catalyzes the condensation of serine with homocysteine to form cystathionine and occupies a crucial regulatory position between the methionine cycle and transsulfuration. The human cystathionine ␤-synthase gene promoters ؊1a and ؊1b are expressed in a limited number of tissues and are coordinately regulated with proliferation through a redox-sensitive mechanism. Site-directed mutagenesis, DNase I footprinting and deletion analysis of 5276 bp of 5 proximal ؊1b flanking sequence revealed that this region does not confer tissue-specific expression and that 210 bp of proximal sequence is sufficient for maximal promoter activity. As little as 32 bp of the ؊1b proximal promoter region is capable of driving transcription in HepG2 cells, and this activity is entirely dependent upon the presence of a single overlapping Sp1/Egr1 binding site. Co-transfection studies in Drosophila SL2 cells indicated that both promoters are transactivated by Sp1 and Sp3 but only the ؊1b promoter is subject to a site-specific synergistic regulatory interaction between Sp1 and Sp3. Sp1-deficient fibroblasts expressing both Sp3 and NF-Y were negative for CBS activity. Transfection of these cells with a mammalian Sp1 expression construct induced high levels of CBS activity indicating that Sp1 has a critical and indispensable role in the regulation of cystathionine ␤-synthase. Sp1 binding to both CBS promoters is sensitive to proliferation status and is negatively regulated by Kruppel-like factors in co-transfection experiments suggesting a possible mechanism for the tissue specific regulation of cystathionine ␤-synthase.

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Transcriptional regulation of the cystathionine-β-synthase gene in Down syndrome and non–Down syndrome megakaryocytic leukemia cell lines

Cited by 45 publications

References 20 publications

Rat pancreatic level of cystathionine γ-lyase is regulated by glucose level via specificity protein 1 (SP1) phosphorylation

Rat pancreatic level of cystathionine γ-lyase is regulated by glucose level via specificity protein 1 (SP1) phosphorylation

The Role of Cytidine Deaminase and GATA1 Mutations in the Increased Cytosine Arabinoside Sensitivity of Down Syndrome Myeloblasts and Leukemia Cell Lines

The Dominant Role of Sp1 in Regulating the Cystathionine β-Synthase –1a and –1b Promoters Facilitates Potential Tissue-specific Regulation by Kruppel-like Factors

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