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Youssef, Jihan; Badr, Mostafa Z.

doi:10.1186/1476-4598-2-3

Mol Cancer

2003

DOI: 10.1186/1476-4598-2-3

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Jihan Youssef

Mostafa Z. Badr

Abstract: Background: Glucocorticoids inhibit hepatocellular proliferation and modulate the expression of oncogenes and tumor suppressor genes via mechanisms involving the glucocorticoid receptor. Glucocorticoids also produce a receptor-mediated inhibitory effect on both basal and hormonestimulated expression of a newly discovered family of molecules important for shutting off cytokine action. We therefore hypothesized that inhibiting glucocorticoid receptors may disturb hepatocellular growth and apoptosis. Consequently… Show more

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Cited by 8 publications

References 32 publications

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Mechanism for 12 Hr Rhythm Generation by the Circadian Clock

Westermark

Herzel

2013

Cell Reports

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In addition to the well-known circadian rhythms in animal behavior, cell biology, and gene expression, there are also 12 hr rhythms. The mechanism giving rise to these 12 hr rhythms is not clear. We worked with the hypothesis that observed 12 hr rhythms in gene expression are the results of an interplay between components of the circadian clock. Analysis of mouse liver expression data indeed revealed a strong circadian component in observed 12 hr gene expression rhythms. We show theoretically that pairs of circadian transcription factors with certain circadian phase relationships can give rise to these 12 hr rhythms, if binding noncompetitively to the promoters of regulated genes. We took an inventory of circadian transcription factors in mouse liver using available microarray data and matched these to predicted binding sites in the promoters of genes displaying 12 hr rhythms. Binding sites for transcription factor pairs with phase relationships predicted by theory were overrepresented in these promoters.

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Mechanism for 12 Hr Rhythm Generation by the Circadian Clock

Westermark

Herzel

2013

Cell Reports

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The tobacco carcinogen NNK drives accumulation of DNMT1 at the GR promoter thereby reducing GR expression in untransformed lung fibroblasts

Taylor

Wheeler

Singh

et al. 2018

Sci Rep

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Small cell lung cancer (SCLC) is a highly aggressive, predominantly cigarette smoke-induced tumour with poor prognosis. The glucocorticoid receptor (GR), a SCLC tumour suppressor gene, is typically reduced in SCLC. We now show that SCLC cells express high levels of DNA methyltransferase 1 (DNMT1) which accumulates at the GR promoter. DNMT1 expression is further increased by exposure to the tobacco carcinogen NNK. In the untransformed human lung fibroblast cell line, MRC-5, short term NNK treatment decreases GRα mRNA and protein expression due to accumulation of DNMT1 at the GR promoter. Long term NNK treatment results in persistently augmented DNMT1 levels with lowered GR levels. Long term exposure to NNK slows cell proliferation and induces DNA damage, while the GR antagonist RU486 stimulates proliferation and protects against DNA damage. Although both NNK and RU486 treatment increases methylation at the GR promoter, neither are sufficient to prevent senescence in this context. NNK exposure results in accumulation of DNMT1 at the GR promoter in untransformed lung cells mimicking SCLC cells, directly linking tobacco smoke exposure to silencing of the GR, an important step in SCLC carcinogenesis.

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Altered Expression of p53 mRNA in the Brain and Pituitary During Repeated Immobilization Stress: Negative Correlation with Glucocorticoid Receptor mRNA Levels

Nishimura

Makino

Tanaka

et al. 2004

J Neuroendocrinology

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In our previous study, apparent reduction of glucocorticoid receptor (GR) mRNA was seen in the hippocampus and the hypothalamic paraventricular nucleus (PVN) during repeated immobilization (IMO) stress, but not following starvation. Our laboratory has also shown that the sp1 activates, whereas tumour suppressor p53 represses the promoter activity of GR gene. In an attempt to reveal the possibility that transcription factors such as sp1 and/or p53 are involved in the regulation of GR mRNA expression in the hippocampus and in the PVN in vivo, we examined the expression of GR mRNA, p53 mRNA, and sp1 mRNA in the hippocampus and in the PVN during repeated IMO and following starvation. In addition, the expression of these mRNAs was examined in the anterior pituitary, another GR-rich area. GR mRNA in all subfields of the hippocampus was robustly decreased, while GR mRNA in the anterior pituitary was increased, 24 h following 4 x IMO (2 h daily, for 4 consecutive days) and immediately after 5 x IMO. GR mRNA in the PVN was significantly decreased immediately after 5 x IMO, but not at 24 h after 4 x IMO. Conversely, p53 mRNA in the PVN and hippocampus was increased, whereas p53 mRNA in the anterior pituitary was decreased, 24 h following 4 x IMO and immediately after 5 x IMO. Sp1 mRNA was unchanged in all areas examined following repeated IMO. Following 4 days of starvation, neither GR mRNA, p53 mRNA nor sp1 mRNA showed any changes in the PVN and the hippocampus, except there was a minor decrease in GR mRNA in CA1-2. In the anterior pituitary, 4 days of starvation induced a minor, but significant increase in GR mRNA, whereas it decreased p53 mRNA. Overall, regression analyses revealed a negative correlation between GR mRNA levels and p53 mRNA levels in CA1-2 and dentate gyrus of the hippocampus and in the anterior pituitary. GR mRNA in the PVN also showed a tendency towards the negative correlation with p53 mRNA levels. The results raise the possibility that p53 negatively regulates GR mRNA expression in the PVN, the hippocampus and the anterior pituitary during repeated immobilization stress.

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Untitled

Cited by 8 publications

References 32 publications

Mechanism for 12 Hr Rhythm Generation by the Circadian Clock

Mechanism for 12 Hr Rhythm Generation by the Circadian Clock

The tobacco carcinogen NNK drives accumulation of DNMT1 at the GR promoter thereby reducing GR expression in untransformed lung fibroblasts

Altered Expression of p53 mRNA in the Brain and Pituitary During Repeated Immobilization Stress: Negative Correlation with Glucocorticoid Receptor mRNA Levels

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