Down-Regulation by Nuclear Factor κB of Human 25-Hydroxyvitamin D3 1α-Hydroxylase Promoter

Ebert, Regina; Jovanovic, Marlena; Ulmer, Matthias; Schneider, Doris; Meissner‐Weigl, Jutta; Adamski, Jerzy; Jakob, Franz

doi:10.1210/me.2002-0441

Cited by 48 publications

(37 citation statements)

References 21 publications

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“…Further studies are required to identify the CRE binding protein and its role in repression. There is recent evidence that NFkB can down regulate the CYP27B1 promoter in human embryonic 293 cells through a site in the CYP27B1 proximal promoter at -92 to -83 (Ebert et al 2004). While this site clearly plays no role in the upstream repression phenomenon reported in the current work, it is possible that an NFkB site located in the far upstream region may be involved in repression, although such a site would be expected to contribute in only a minor way.…”

Section: Discussionmentioning

confidence: 52%

Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells

Dwivedi

Anderson²,

Omdahl³

et al. 2005

Endocrine Related Cancer

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The hormone 1,25-dihydroxyvitamin D (1,25D) may play a protective role in prostate cancer. 25-hydroxyvitamin D 1-a hydroxylase (CYP27B1) is the enzyme responsible for the regulation of cellular 1,25D levels. CYP27B1 is substantially repressed in prostate cancer cells. We have investigated the molecular basis for this inhibition. First, we identify a repressive region between -997 and -1200 in the human CYP27B1 promoter following transient transfection analysis in the prostate cancer cell lines DU145, PC3 and LNCaP. Next, we demonstrate a role for the transcription factor growth factor independent-1 (GFI1) in the repression of CYP27B1. Electrophoretic mobility assays with nuclear extracts from prostate cancer cell lines established binding of GFI1 to the sequence 5k-TGGTACAATCATAACTCACTGCAG-3k present at -997 to -1200 in the repressive region. Site directed mutagenesis of the core GFI1 binding sequence (5k-AATC-3k) substantially increased while forced expression of GFI1 decreased the expression of the CYP27B1 reporter construct. Importantly, GFI1 repression is dependent on an intact GFI1 binding site in the -997 to -1200 region. GFI1 is an oncoprotein known to form a large protein complex with co-repressors that recruit histone deacetylases. We propose that the formation of such a repressive complex on the inhibitory domain of the CYP27B1 gene in prostate cancer cells could lead to silencing of either the nearby enhancer or proximal promoter domains and lead to cancer progression by reducing local production of 1,25D. These studies provide the basis for a more detailed understanding of CYP27B1 repression in prostate cancer cells and could provide a novel insight in future diagnosis and treatment.

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Section: Discussionmentioning

confidence: 52%

Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells

Dwivedi

Anderson²,

Omdahl³

et al. 2005

Endocrine Related Cancer

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“…Although aldosterone activates NFkB, spironolactone additionally inhibits NFkB in a MR-independent manner [51,52]. NFkB represses 25-hydroxyvitamin D 3 1-alpha-hydroxylase expression and treatment of HEK293 cells with an NFkB inhibitor increases Cyp27b1 expression [53]. In addition to blocking the effects of aldosterone, spironolactone could therefore increase Cyp27b1 expression and subsequent klotho expression by inhibiting NFkB activity independent of the mineralocorticoid receptor.…”

Section: Discussionmentioning

confidence: 99%

25-Hydroxyvitamin D₃1-Alpha-Hydroxylase-Dependent Stimulation of Renal Klotho Expression by Spironolactone

Alesutan

Feger

Pakladok

et al. 2013

Kidney Blood Press Res

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Background: Klotho, a transmembrane protein, protease and hormone mainly expressed in kidney, is required for the suppression of 1,25(OH)₂D₃-generating 25-hydroxyvitamin D₃ 1-alpha-hydroxylase (Cyp27b1) by FGF23. Conversely, 1,25(OH)₂D₃ stimulates, by activating the vitamin D₃ receptor (Vdr), the expression of klotho, thus establishing a negative feedback loop. Klotho protects against renal and vascular injury. Klotho deficiency accelerates aging and early death, effects at least partially due to excessive formation of 1,25(OH)₂D₃ and subsequent hyperphosphatemia. Klotho expression is inhibited by aldosterone. The present study explored the interaction of aldosterone and DOCA as well as the moderately selective mineralocorticoid receptor antagonist spironolactone on klotho expression. Methods: mRNA levels were determined utilizing quantitative RT-PCR in human embryonic kidney cells (HEK293) or in renal tissues from mice without or with prior mineralocorticoid (aldosterone or DOCA) and/or spironolactone treatment. In HEK293 cells, protein levels were determined by western blotting. The experiments in HEK293 cells were performed without or with silencing of CYP27B1, of vitamin D₃ receptor (VDR) or of mineralocorticoid receptor (NR3C2). Results: In HEK293 cells aldosterone and in mice DOCA significantly decreased KLOTHO gene expression, effects opposed by spironolactone treatment. Spironolactone treatment alone significantly increased KLOTHO and CYP27B1 transcript levels in HEK293 cells (24 hours) and mice (8 hours or 5 days). Moreover, spironolactone significantly increased klotho and CYP27B1 protein levels in HEK293 cells (48 hours). Reduced NR3C2 expression following silencing did not significantly affect KLOTHO and CYP27B1 transcript levels in presence or absence of spironolactone. Silencing of CYP27B1 and VDR significantly blunted the stimulating effect of spironolactone on KLOTHO mRNA levels in HEK293 cells. Conclusion: Besides blocking the effects of aldosterone, spironolactone upregulates KLOTHO gene expression by upregulation of 25-hydroxyvitamin D₃ 1-alpha-hydroxylase with subsequent activation of the vitamin D₃ receptor by 1,25(OH)₂D₃, an effect possibly independent from the mineralocorticoid receptor.

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“…Calcium solubility may be impaired in CKD either due to impaired protein digestion [42], uremic and iatrogenic hypochlorhydria [43], or altered intestinal transit. Recent evidence points to oxidative stress, already present in incipient nephropathy [44], as a potential mediator of vitamin D hyporesponsiveness in (early) CKD [45]. …”

Section: Discussionmentioning

confidence: 99%

Evidence in Favor of a Severely Impaired Net Intestinal Calcium Absorption in Patients with (Early-Stage) Chronic Kidney Disease

Viaene¹,

Meijers²,

Vanrenterghem³

et al. 2012

Am J Nephrol

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Introduction: Calcium and phosphorus are essential to many vital physiological processes. Little is known about the net and fractional intestinal absorption of calcium and phosphorus in patients with chronic kidney disease (CKD) and their clinical and hormonal determinants. Methods: Blood and 24-hour urine samples were collected in 20 healthy volunteers (HV) and 72 stable CKD stage 1–4 patients and analyzed for parameters of mineral metabolism including calcidiol, calcitriol, and parathyroid hormone (PTH). Dietary intake was assessed by dietary history. Results: The 24-hour urinary calcium excretion, as opposed to the phosphorus excretion, showed a stepwise decrease across CKD stages (median of 219, 84, 40, and 22 mg/day in HV and patients with CKD stages 1–2, 3 and 4, respectively). Younger age, high serum calcitriol, and high estimated GFR were associated with a high 24-hour urinary calcium excretion. High serum calcitriol levels and dietary phosphorus intake were associated with a high 24-hour urinary phosphorus excretion. The fractional intestinal calcium absorption, as estimated by the urinary-to-ingested calcium ratio, decreased across CKD stages. Conclusions: The 24-hour urinary excretion of calcium, as opposed to phosphorus, is markedly decreased in CKD, even in early-stage disease. This is partly explained by low calcitriol levels and older age. Assuming a neutral calcium balance at the time of urine collection, we infer that net intestinal calcium absorption may be severely impaired in CKD.

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Down-Regulation by Nuclear Factor κB of Human 25-Hydroxyvitamin D3 1α-Hydroxylase Promoter

Cited by 48 publications

References 21 publications

Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells

Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells

25-Hydroxyvitamin D₃1-Alpha-Hydroxylase-Dependent Stimulation of Renal Klotho Expression by Spironolactone

Evidence in Favor of a Severely Impaired Net Intestinal Calcium Absorption in Patients with (Early-Stage) Chronic Kidney Disease

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Down-Regulation by Nuclear Factor κB of Human 25-Hydroxyvitamin D3 1α-Hydroxylase Promoter

Cited by 48 publications

References 21 publications

Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells

Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells

25-Hydroxyvitamin D31-Alpha-Hydroxylase-Dependent Stimulation of Renal Klotho Expression by Spironolactone

Evidence in Favor of a Severely Impaired Net Intestinal Calcium Absorption in Patients with (Early-Stage) Chronic Kidney Disease

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25-Hydroxyvitamin D₃1-Alpha-Hydroxylase-Dependent Stimulation of Renal Klotho Expression by Spironolactone