Mechanisms regulating the cadmium-mediated suppression of Sp1 transcription factor activity in alveolar epithelial cells

Watkin, R D; Nawrot, Tim S.; Potts, Ryan; Hart, Beth A.

doi:10.1016/s0300-483x(02)00577-2

Cited by 69 publications

(45 citation statements)

References 49 publications

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“…Our results are, in fact, consistent with data from other systems showing that Sp1 binding is repressed by phosphorylation and that removal of phosphate groups from Sp1 enhances binding to DNA (33)(34)(35)(36)(37)(38)(39). However, it is possible that phosphorylation of Sp1 or Sp1-like proteins could enhance the ability of Sp1 to form an active transcriptional complex with other nuclear factors.…”

Section: Sp1 Is Required For the Elevated Levels Of Ctgf Expression Osupporting

confidence: 82%

Constitutive Connective Tissue Growth Factor Expression in Scleroderma Fibroblasts Is Dependent on Sp1

Holmes

Abraham

Chen

et al. 2003

Journal of Biological Chemistry

109

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Fibrotic diseases such as scleroderma (systemic sclerosis, SSc) are characterized by an excessive production of extracellular matrix and profibrotic proteins such as connective tissue growth factor (CTGF). In normal dermal fibroblasts, CTGF is not expressed unless induced by proteins such as tumor growth factor-␤ (TGF␤). Conversely, in fibroblasts cultured from fibrotic lesions CTGF mRNA and protein are constitutively expressed, even in the absence of exogenously added TGF␤. Thus, studying the mechanism underlying CTGF overexpression in SSc fibroblasts is likely to yield valuable insights into the basis of the fibrotic phenotype of SSc and possibly other scarring disease. CTGF overexpression is mediated primarily by sequences in the CTGF promoter. In this report, we identify the minimal promoter element involved with the overexpression of CTGF in SSc fibroblasts. This element is distinct from the element necessary and sufficient for the induction of CTGF expression by TGF␤ in normal fibroblasts. Within this region is a functional Sp1 binding site. Blocking Sp1 activity reduces the elevated, constitutive levels of CTGF promoter activity and protein expression observed in SSc fibroblasts. Relative to those prepared from normal dermal fibroblasts, nuclear extracts prepared from SSc fibroblasts possess increased Sp1 binding activity. Removal of phosphate groups from nuclear extracts enhanced Sp1 binding activity, suggesting that phosphorylation of Sp1 normally reduces Sp1 binding to DNA. Thus, the constitutive overexpression of CTGF in SSc fibroblasts seems to be independent of TGF␤ signaling but dependent at least in part on Sp1.

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Section: Sp1 Is Required For the Elevated Levels Of Ctgf Expression Osupporting

confidence: 82%

Constitutive Connective Tissue Growth Factor Expression in Scleroderma Fibroblasts Is Dependent on Sp1

Holmes

Abraham

Chen

et al. 2003

Journal of Biological Chemistry

109

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“…However, exposure to toxic metals in animal studies has usually been much higher than those reported in humans environmentally exposed to toxic metals. Third, several in vitro studies have shown plausible toxicodynamic pathways, such as increased oxidative stress (as reviewed in this special issue by Cuypers et al 2010), modified activity of transcription factors (Watkin et al 2003), and inhibition of DNA repair . Most errors that arise during DNA replication can be corrected by DNA polymerase proof reading or by postreplication mismatch repair.…”

Section: Cancermentioning

confidence: 99%

Cadmium exposure in the population: from health risks to strategies of prevention

et al. 2010

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We focus on the recent evidence that elucidates our understanding about the effects of cadmium (Cd) on human health and their prevention. Recently, there has been substantial progress in the exploration of the shape of the Cd concentrationresponse function on osteoporosis and mortality. Environmental exposure to Cd increases total mortality in a continuous fashion without evidence of a threshold, independently of kidney function and other classical factors associated with mortality including age, gender, smoking and social economic status. Pooled hazard rates of two recent environmental population based cohort studies revealed that for each doubling of urinary Cd concentration, the relative risk for mortality increases with 17% (95% CI 4.2-33.1%; P \ 0.0001). Tubular kidney damage starts at urinary Cd concentrations ranging between 0.5 and 2 lg urinary Cd/g creatinine, and recent studies focusing on bone effects show increased risk of osteoporosis even at urinary Cd below 1 lg Cd/g creatinine. The non-smoking adult population has urinary Cd concentrations close to or higher than 0.5 lg Cd/g creatinine. To diminish the transfer of Cd from soil to plants for human consumption, the bioavailability of soil Cd for the plants should be reduced (external bioavailability) by maintaining agricultural and garden soils pH close to neutral (pH-H 2 O of 7.5; pH-KCL of 6.5). Reducing the systemic bioavailability of intestinal Cd can be best achieved by preserving a balanced iron status. The latter might especially be relevant in groups with a lower intake of iron, such as vegetarians, and women in reproductive phase of life. In exposed populations, house dust loaded with Cd is an additional relevant exposure route. In view of the insidious etiology of health effects associated with low dose exposure to Cd and the current European Cd intake which is close to the tolerable weekly intake, one should not underestimate the importance of the recent epidemiological evidence on Cd toxicity as to its medical and public health implications.

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“…29 However, exposure to toxic metals in animal studies have usually been much higher than those reported for human beings who had been environmentally exposed to toxic metals. 30 Third, several studies done in vitro have shown plausible pathways such as increased oxidative stress, 29 modified activity of transcription factors, 31 and inhibition of DNA repair. 32,33 However, the role of these pathways in the response to toxic-metal exposure has not been defined in human beings.…”

Section: Discussionmentioning

confidence: 99%

Environmental exposure to cadmium and risk of cancer: a prospective population-based study

Nawrot

Plusquin

Hogervorst

et al. 2006

The Lancet Oncology

537

288

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SummaryBackground Cadmium is a ubiquitous environmental pollutant, which accumulates in the human body such that 24-h urinary excretion is a biomarker of lifetime exposure. We aimed to assess the association between environmental exposure to cadmium and cancer.Methods We recruited a random population sample (n=994) from an area close to three zinc smelters and a reference population from an area with low exposure to cadmium. At baseline (1985-89), we measured cadmium in urine samples obtained over 24 h and in the soil of participants' gardens, and followed the incidence of cancer until June 30, 2004. We used Cox regression to calculate hazard ratios for cancer in relation to internal (ie, urinary) and external (ie, soil) exposure to cadmium, while adjusting for covariables.

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Mechanisms regulating the cadmium-mediated suppression of Sp1 transcription factor activity in alveolar epithelial cells

Cited by 69 publications

References 49 publications

Constitutive Connective Tissue Growth Factor Expression in Scleroderma Fibroblasts Is Dependent on Sp1

Constitutive Connective Tissue Growth Factor Expression in Scleroderma Fibroblasts Is Dependent on Sp1

Cadmium exposure in the population: from health risks to strategies of prevention

Environmental exposure to cadmium and risk of cancer: a prospective population-based study

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