The Glucocorticoid-responsive Gene Cascade

Gotoh, Tomomi; Chowdhury, Shantanu; Takao, Masaki; Mori, Masataka

doi:10.1074/jbc.272.6.3694

Cited by 93 publications

(34 citation statements)

References 50 publications

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“…This conclusion does not rule out the possibility that de novo synthesis of a factor(s) is necessary to realize a full response. The expression of C/EBP␣ and -␤ is, for example, rapidly induced by glucocorticoids and cAMP and is involved in the hormone-induced expression of several genes (9,10,20,39,50). A crucial role for members of the C/EBP family of transcription factors in achieving the full response of the GRU fits with our observation that the C/EBP site within the GRU is essential for the function of the unit and, hence, for the activation by glucocorticoids.…”

Section: Discussionsupporting

confidence: 65%

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Glucocorticoid Receptor, C/EBP, HNF3, and Protein Kinase A Coordinately Activate the Glucocorticoid Response Unit of the Carbamoylphosphate Synthetase I Gene

Christoffels

Grange

Kaestner

et al. 1998

Molecular and Cellular Biology

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A single far-upstream enhancer is sufficient to confer hepatocyte-specific, glucocorticoid-and cyclic AMPinducible periportal expression to the carbamoylphosphate synthetase I (CPS) gene. To identify the mechanism of hormone-dependent activation, the composition and function of the enhancer have been analyzed. DNase I protection and gel mobility shift assays revealed the presence of a cyclic AMP response element, a glucocorticoid response element (GRE), and several sites for the liver-enriched transcription factor families HNF3 and C/EBP. The in vivo relevance of the transcription factors interacting with the enhancer in the regulation of CPS expression in the liver was assessed by the analysis of knockout mice. A strong reduction of CPS mRNA levels was observed in glucocorticoid receptor-and C/EBP␣-deficient mice, whereas the CPS mRNA was normally expressed in C/EBP␤ knockout mice and in HNF3␣ and -␥ double-knockout mice. (The role of HNF␤ could not be assessed, because the corresponding knockout mice die at embryonic day 10). In hepatoma cells, most of the activity of the enhancer is contained within a 103-bp fragment, which depends for its activity on the simultaneous occupation of the GRE, HNF3, and C/EBP sites, thus meeting the requirement of a glucocorticoid response unit. In fibroblast-like CHO cells, on the other hand, the GRE in the CPS enhancer does not cooperate with the C/EBP and HNF3 elements in transactivation of the CPS promoter. In both hepatoma and CHO cells, stimulation of expression by cyclic AMP depends mainly on the integrity of the glucocorticoid pathway, demonstrating cross talk between this pathway and the cyclic AMP (protein kinase A) pathway.

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Section: Discussionsupporting

confidence: 65%

“…The glucocorticoid-induced activation of the CPS enhancer fragment that lacks the GRE (Fig. 4, construct 4), on the other hand, may well be indirect and reflect glucocorticoidinduced expression of transcription factors such as C/EBP (9,20), for which binding sites are present in the CRE-containing fragment.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid Receptor, C/EBP, HNF3, and Protein Kinase A Coordinately Activate the Glucocorticoid Response Unit of the Carbamoylphosphate Synthetase I Gene

Christoffels

Grange

Kaestner

et al. 1998

Molecular and Cellular Biology

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“…The present findings of a dramatic fall in the expression of CPS and arginase genes in the livers of C/EBP␣-deficient mice are consistent with these previous observations and underline the importance of C/EBP␣ in the regulation of the expression of these two genes. However, our previous studies have shown that C/EBP␤ rather than C/EBP␣ activates the arginase promoter more strongly (12) and is more crucial for stimulation of the arginase enhancer in response to glucocorticoids (13,40). Thus, it is likely that C/EBP␣ is involved in basal level expression of the gene, whereas C/EBP␤ is important for high level expression of the arginase gene induced by glucocorticoids in response to dietary changes, etc.…”

Section: Discussionmentioning

confidence: 94%

Hypoglycemia-associated Hyperammonemia Caused by Impaired Expression of Ornithine Cycle Enzyme Genes in C/EBPα Knockout Mice

Kimura¹,

Christoffels²,

Chowdhury³

et al. 1998

Journal of Biological Chemistry

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Ammonia produced by amino acid metabolism is detoxified through conversion into urea by the ornithine cycle in the liver, whereas carbon skeletons of amino acids are converted to glucose by gluconeogenic enzymes. Promoter and enhancer sequences of several genes for ornithine cycle enzymes interact with members of the CCAAT/ enhancer-binding protein (C/EBP) transcription factor family. Disruption of the C/EBP␣ gene in mice causes hypoglycemia associated with the impaired expression of gluconeogenic enzymes. Here we examined the expression of ornithine cycle enzyme genes in the livers of C/EBP␣-deficient mice. mRNA levels for the first, third, fourth, and fifth enzymes of five enzymes in the cycle were decreased in C/EBP␣-deficient mice. Protein levels for the first, second, fourth, and fifth enzymes were also decreased. In situ hybridization analysis revealed that the enzyme mRNAs were distributed normally in the periportal region but were disordered in C/EBP␣-deficient mice with relatively higher mRNA levels in the midlobular region. Blood ammonia concentrations in the mutant mice were severalfold higher than in wild-type mice. Thus, C/EBP␣ is crucial for ammonia detoxification by ornithine cycle enzymes and for coordination of gluconeogenesis and urea synthesis.Urea synthesis and gluconeogenesis, representative traits of the liver, are closely related to each other with regard to amino acid metabolism. Deamination of the ␣-amino group of amino acids produces ammonia, a toxic metabolite that is detoxified by conversion into urea via the ornithine cycle in the liver. On the other hand, carbon skeletons derived from deaminated amino acids are primarily converted into glucose by gluconeogenic enzymes. Besides this relationship, the ornithine cycle and the gluconeogenic pathway are correlated by sharing common steps in two enzymatic reactions (1). Reflecting these close relationships, genes for both pathways are regulated in a coordinate manner. Urea synthesis and gluconeogenesis are induced in the perinatal period and postnatally are up-or downregulated by dietary changes, generally in the same direction (reviewed in Refs. 2-5). These responses are mediated mainly by hormones. Glucagon and glucocorticoids stimulate, whereas insulin represses, the expression of genes for both pathways (2-5).Studies of transcriptional regulation of genes for five enzymes of the ornithine cycle revealed the architecture of regulatory regions such as the promoter and enhancer (reviewed in Ref.3). In the promoter region of the first enzyme, carbamylphosphate synthetase (CPS) 1 (6), the enhancer region of the second enzyme, ornithine transcarbamylase (OTC) (7-9), and the promoter and enhancer regions of the last enzyme, arginase (10 -13), there are binding sites for members of the CCAAT/ enhancer-binding protein (C/EBP) family (14, 15). C/EBP␣ (16) is the original member of this family and is the prototype of basic leucine zipper transcription factors (17). C/EBP␣ is most enriched in the liver and adipose tissues (18) and has been implic...

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“…Sucraseisomaltase may represent a secondary response gene because its induction by steroids is delayed (22). Steroids are capable of inducing the synthesis of several transcription factors, including C/EBP-␣, C/EBP-␤, C/EBP-␥, and IB, which in turn may influence the downstream expression of a group of secondary response genes (7,12). Although both C/EBP-␤ and C/EBP-␥ mRNA transcripts have been detected in the intestine, only C/EBP-␣ has been identified immunohistochemically in terminally differentiated cells of the villus (28).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional control of the murine polymeric IgA receptor promoter by glucocorticoids

Wang

Lam

et al. 1999

American Journal of Physiology-Gastrointestinal and Liver Physi

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Glucocorticoids have been implicated as an important regulator of intestinal epithelial cell ontogeny. The polymeric IgA receptor (pIgR) is expressed in the intestinal epithelial layer and is regulated by several mediators, including glucocorticoids. The mechanism of how corticosteroids alter the transcriptional regulation of pIgR expression has not been defined. In this study, we demonstrated that glucocorticoids upregulate steady-state pIgR mRNA levels in the proximal intestine of suckling rats and in the IEC-6 intestinal cell line. We performed functional analysis of the 5′-flanking region in the presence of glucocorticoids and its receptor using the intestinal cell line Caco-2. We screened 4.7 kb of the upstream region of the murine gene and identified the most potent steroid response element to reside between nt −215 and −163 relative to the start of transcription. Substitution mutation analysis of this region identified the location of the putative steroid response element to be between nt −195 and −176. In vitro DNase I footprint analysis using the recombinant glucocorticoid receptor DNA binding domain confirmed a single area of protection that spans the nt identified by mutagenesis analysis. Electrophoretic mobility shift assays of the putative element confirmed the binding of both recombinant and cell synthesized glucocorticoid receptor in a specific manner. In summary, we report the identification and characterization of the glucocorticoid-DNA response element located in the immediate 5′-upstream region of the murine pIgR gene.

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The Glucocorticoid-responsive Gene Cascade

Cited by 93 publications

References 50 publications

Glucocorticoid Receptor, C/EBP, HNF3, and Protein Kinase A Coordinately Activate the Glucocorticoid Response Unit of the Carbamoylphosphate Synthetase I Gene

Glucocorticoid Receptor, C/EBP, HNF3, and Protein Kinase A Coordinately Activate the Glucocorticoid Response Unit of the Carbamoylphosphate Synthetase I Gene

Hypoglycemia-associated Hyperammonemia Caused by Impaired Expression of Ornithine Cycle Enzyme Genes in C/EBPα Knockout Mice

Transcriptional control of the murine polymeric IgA receptor promoter by glucocorticoids

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