Influenza Virus Infection Induces Metallothionein Gene Expression in the Mouse Liver and Lung by Overlapping but Distinct Molecular Mechanisms

Ghoshal, Kalpana; Majumder, Sarmila; Zhu, Qin; Hunzeker, John; Datta, Jharna; Shah, Manisha; Sheridan, John F.; Jacob, Samson T.

doi:10.1128/mcb.21.24.8301-8317.2001

Cited by 63 publications

(54 citation statements)

References 71 publications

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“…In Vivo Genomic Footprinting-In vivo genomic footprinting of the human SMN promoter was performed as described (40,41). The human SMN promoter was amplified by ligation-mediated PCR (LM-PCR) according to the procedure of Mueller and Wold (42).…”

Section: Methodsmentioning

confidence: 99%

Identification of a Novel Cyclic AMP-response Element (CRE-II) and the Role of CREB-1 in the cAMP-induced Expression of the Survival Motor Neuron (SMN) Gene

Majumder

Varadharaj

Ghoshal

et al. 2004

Journal of Biological Chemistry

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Spinal muscular atrophy, an autosomal recessive disorder, is caused by loss of the SMN1 (survival motor neuron) gene while retaining the SMN2 gene. SMN1 produces a majority of full-length SMN transcript, whereas SMN2 generates mostly an isoform lacking exon 7. Here, we demonstrate a novel cAMP-response element, CRE-II, in the SMN promoter that interacts with the cAMP-response element-binding (CREB) family of proteins. In vitro DNase I protection analysis and in vivo genomic footprinting of the SMN promoter using the brain and liver nuclei from SMN2 transgenic mice revealed footprinting at the CRE-II site. Site-directed mutation of the CRE-II element caused a marked reduction in the SMN promoter activity revealed by transient transfection assay. Activation of the cAMP pathway by dibutyryl cAMP (0.5 mM) alone or in combination with forskolin (20 M) caused a 2-5-fold increase in the SMN promoter activity but had no effect on the CRE-II mutated promoter. Electrophoretic mobility shift assay and a UV-induced DNA-protein crosslinking experiment confirmed that CREB1 binds specifically to the CRE-II site. Transient overexpression of CREB1 protein resulted in a 4-fold increase of the SMN promoter activity. Intraperitoneal injection of epinephrine in mice expressing two copies of the human SMN2 gene resulted in a 2-fold increase in full-length SMN transcript in the liver. Combined treatment with dibutyryl cAMP and forskolin significantly increased the level of both the full-length and exon 7-deleted SMN (exon⌬7SMN) transcript in primary hepatocytes from mice expressing two copies of human SMN2 gene. Similar treatments of type I spinal muscular atrophy mouse and human fibroblasts as well as HeLa cells resulted in an augmented level of SMN transcript. These findings suggest that the CRE-II site in SMN promoter positively regulates the expression of the SMN gene, and treatment with cAMP-elevating agents increases expression of both the full-length and exon⌬7SMN transcript.

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Section: Methodsmentioning

confidence: 99%

Identification of a Novel Cyclic AMP-response Element (CRE-II) and the Role of CREB-1 in the cAMP-induced Expression of the Survival Motor Neuron (SMN) Gene

Majumder

Varadharaj

Ghoshal

et al. 2004

Journal of Biological Chemistry

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“…These are all strong inducers of these genes (21,22). MT gene expression is also up-regulated in animals under stress (23), in response to viral infection (24) and in Cu,Zn-superoxide dismutase null mice (25). By virtue of their heavy metal binding capacity, MTs participate in maintaining cellular homeostasis of biologically essential metals such as Zn 2ϩ and Cu 1ϩ .…”

mentioning

confidence: 99%

Role of de Novo DNA Methyltransferases and Methyl CpG-binding Proteins in Gene Silencing in a Rat Hepatoma

Majumder

Ghoshal

Datta

et al. 2002

Journal of Biological Chemistry

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The expression of metallothionein-I (MT-I), a known antioxidant, was suppressed in a transplanted rat hepatoma because of promoter methylation and was induced by heavy metals only after demethylation by 5-azacytidine (5-AzaC). Treatment of the tumor-bearing rats with 5-AzaC resulted in significant regression of the hepatoma. When the inhibitor-treated tumor was allowed to grow in a new host, MT-I promoter was remethylated, which suggested de novo methylation. The activities of both de novo (3-fold) and maintenance DNA methyltransferases (DNMT) (5-fold) were higher in the hepatoma than in the host liver. The mRNA levels of the de novo methyltransferases DNMT3a and DNMT3b were 3-and 6-fold higher, respectively, in the tumor implicating transcriptional up-regulation of these two genes in this tissue. Immunohistochemical analysis showed exclusive localization of DNMT3a in the nuclei of both the liver and hepatoma, whereas DNMT3b was detected in the nuclei as well as the cytoplasm. Immunoblot assay showed that the levels of DNMT1, DNMT3a, and DNMT3b proteins in the hepatoma were 5-, 10-, and 4-fold higher, respectively, than in the liver. The mRNA level of the major methyl CpG-binding protein (MeCP2) was 8-fold higher in the tumor compared with the liver. Immunohistochemical studies showed that MeCP2 is localized exclusively in the nuclei of both tissues. A chromatin immunoprecipitation assay demonstrated that MeCP2 was associated with the MT-I promoter in the hepatoma implicating its involvement in repressing the methylated promoter. Analysis of the DNA isolated from the liver and hepatoma by RLGS-M (restriction landmark genomic scanning with methylation-sensitive enzyme) (NotI) showed that many genes in addition to MT-I were methylated in the hepatoma. These data demonstrate suppression of the MT-I gene and probably other genes in a solid tumor by promoter methylation and have provided potential molecular mechanisms for the altered methylation profile of the genes in this tumor.

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“…This effect can be repressed by RU486, suggesting a direct role for GR in viral induction of these proteins. In addition, influenza virus has been shown to enhance GR binding to the promoter of these genes (Ghoshal et al 2001).…”

Section: Effect Of Viral Proteins On Grmentioning

confidence: 99%

“…Inhibits GR activity Chen et al 2000 Influenza virus Increases GR activity Ghoshal et al 2001 HSV-1 Increases GR number and activity Erlandsson et al 2002 Epstein-Barr virus Increases GR number Tomita et al 1985 MCMV Decreases GR binding in spleen Miller et al 1997 Shiga toxin 2 has been shown to increase GR expression, as determined by fluorescence activated cell sorting (FACS) analysis, 24 h after injection, and this is sustained through 48 h. However, the implications of this are not clear, particularly as dexamethasone is not protective at 24 h after injection (Gomez et al 2003). We have recently shown that the anthrax lethal toxin represses GR activity as well as the activity of other nuclear hormone receptors and inhibits the glucocorticoid increase in the liver gluconeogenic enzyme, tyrosine aminotransferase.…”

Section: Effect Referencementioning

confidence: 99%

Role of the hypothalamic-pituitary-adrenal axis, glucocorticoids and glucocorticoid receptors in toxic sequelae of exposure to bacterial and viral products

Webster

Sternberg

2004

Journal of Endocrinology

164

124

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The hypothalamic-pituitary-adrenal (HPA) axis is activated during many bacterial and viral infections, resulting in an increase in circulating glucocorticoid levels. This HPA axis activation and glucocorticoid response are critical for the survival of the host, as demonstrated by the fact that removal of the HPA axis (by adrenalectomy or hypophysectomy) or glucocorticoid receptor (GR) blockade enhances the severity of the infection and in some cases enhances the mortality rate. Replacement with a synthetic glucocorticoid reverses these effects by reducing the severity of the infection and provides protection against lethal effects. In addition, some bacteria and viral infections have been shown to affect the GR directly. These have been described and the implications of such an effect discussed.

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Influenza Virus Infection Induces Metallothionein Gene Expression in the Mouse Liver and Lung by Overlapping but Distinct Molecular Mechanisms

Cited by 63 publications

References 71 publications

Identification of a Novel Cyclic AMP-response Element (CRE-II) and the Role of CREB-1 in the cAMP-induced Expression of the Survival Motor Neuron (SMN) Gene

Identification of a Novel Cyclic AMP-response Element (CRE-II) and the Role of CREB-1 in the cAMP-induced Expression of the Survival Motor Neuron (SMN) Gene

Role of de Novo DNA Methyltransferases and Methyl CpG-binding Proteins in Gene Silencing in a Rat Hepatoma

Role of the hypothalamic-pituitary-adrenal axis, glucocorticoids and glucocorticoid receptors in toxic sequelae of exposure to bacterial and viral products

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