Promoter and 11-kilobase upstream enhancer elements responsible for hepatoma cell-specific expression of the rat ornithine transcarbamylase gene.

Murakami, Takashi; Nishiyori, Atsushi; Takao, Masaki; Mori, Masataka

doi:10.1128/mcb.10.3.1180

Cited by 48 publications

(39 citation statements)

References 68 publications

(87 reference statements)

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“…Through its interaction with C/EBPs, CHOP may participate in the regulation of downstream effector gene transcription during cellular response to amino acid limitation. It has been reported that C/EBP is involved in the transcriptional regulation of the carbamoyl-phosphate synthetase gene and two other urea cycle enzyme genes (47)(48)(49). Therefore, CHOP could play a crucial role in the regulation of nitrogen metabolism under amino acid control, although the cause and effect relationships have to be demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Amino Acid Limitation Induces Expression of CHOP, a CCAAT/Enhancer Binding Protein-related Gene, at Both Transcriptional and Post-transcriptional Levels

Bruhat¹,

Jousse²,

Wang³

et al. 1997

Journal of Biological Chemistry

190

143

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In mammals, plasma concentrations of amino acids are affected by nutritional or pathological conditions. Here we examined the role of amino acid limitation in regulating the expression of CHOP, a CCAAT/enhancer binding protein (C/EBP)-related gene. CHOP protein is capable of interacting with other C/EBPs to modify their DNA binding activities and may function as a negative regulator of these transcription factors. Our data show that leucine limitation in human cell lines leads to induction of CHOP mRNA and protein in a dose-dependent manner. CHOP mRNA induction is rapidly reversed by leucine replenishment. Elevated mRNA levels result from both an increase in the rate of CHOP transcription and an increase in the CHOP mRNA stability. Using a transient expression assay, we show that a promoter fragment, when linked to a reporter gene, is sufficient to mediate the regulation of CHOP expression by leucine starvation in HeLa cells. In addition, we found that decreasing amino acid concentration by itself can induce CHOP expression independently of a cellular stress due to protein synthesis inhibition. Moreover, CHOP expression is induced at leucine concentrations in the range of those observed in blood of protein-restricted animals suggesting that amino acids can participate, in concert with hormones, in the regulation of gene expression.

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Section: Discussionmentioning

confidence: 99%

Amino Acid Limitation Induces Expression of CHOP, a CCAAT/Enhancer Binding Protein-related Gene, at Both Transcriptional and Post-transcriptional Levels

Bruhat¹,

Jousse²,

Wang³

et al. 1997

Journal of Biological Chemistry

190

143

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“…Binding of multiple factors to enhancer regions has been reported for the mouse transthyretin (8), mouse albumin (28), rat muscle creatine kinase (29), and rat ornithine transcarbamylase (40) gene enhancers. Competition experiments in which certain retarded bands appeared to be influenced by the addition of two or three different oligonucleotides as competitors suggest that the binding of some factors to their specific regions occurs cooperatively.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a thyroid-specific enhancer located 5.5 kilobase pairs upstream of the human thyroid peroxidase gene.

Kikkawa¹,

Gonzalez²,

Kimura³

1990

Mol. Cell. Biol.

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A 6.3-kbp segment of DNA, upstream of the human thyroid peroxidase gene, and various deletions thereof were linked to a promoterless bacterial chloramphenicol acetyltransferase reporter gene. These constructs were analyzed by transfection and expression in rat FRTL-5 thyroid cells and in human hepatoma HepG2 cells to localize sequences that are important for thyroid cell-specific expression of the thyroid peroxidase gene. A thyroid-specific enhancer element, capable of activating enhancerless simian virus 40 promoter expression in FRTL-5 cells, was localized to a 230-bp region approximately 5.5 kbp upstream of the human thyroid peroxidase gene transcription start site. DNase I footprinting, using nuclear extracts prepared from FRTL-5 cells, revealed three regions within the 230-bp fragment; none of these regions were protected by nuclear extracts from HepG2 cells. Gel mobility shift assays, using double-stranded oligonucleotides corresponding to the three protected regions, further confirmed the existence of factors in FRTL-5 cells, but not HepG2 cells, able to specifically bind to the enhancer sequences. These results suggest the presence of three cis-acting DNA elements in the human thyroid peroxidase gene enhancer that interact with thyroid-specific trans-acting factors.Regulation of eucaryote genes is accomplished, in part, by the binding of trans-acting protein factors to cis-acting DNA elements. Mechanisms governing tissue-or developmental stage-specific gene regulation have been extensively studied in liver-or muscle-derived cell lines (4, 29, 34). In the case of thyroid tissue, however, little is known about the mechanisms by which thyroid-specific genes are controlled. Transcription of the thyroglobulin gene, whose product is essential to thyroid hormone synthesis (9, 43), is due in part to thyroid-specific (6) and cyclic AMP-responsive (25, 35) DNA elements. However, a thyroid-specific enhancer element has not been described.Thyroid peroxidase (TPO) is a key enzyme involved in thyroid hormone synthesis (9, 43). The cDNAs encoding human (33,36,38) and rat (10, 30) TPO and the human (1, 32) and rat (15) TPO genes have been cloned and sequenced. Recently, studies on human TPO gene promoter activity have been reported which used stable transformants harboring 1.3 kbp of the 5'-flanking sequence connected to a luciferase reporter gene (14) and transient expression of a construct in which 0.9 kbp of TPO upstream DNA was linked to chloramphenicol acetyltransferase (CAT) or growth hormone genes (1). These studies were carried out in dog thyroid cell primary cultures (1). TPO gene promoter activity has also been examined by using the rat TPO gene upstream sequence of 0.4 and 3 kbp in length, fused to the luciferase gene in transient assays (15). Again, these studies did not reveal the presence of an enhancer element responsible for tissue-specific expression in thyroid cells.In this study, we prepared a construct harboring 6.

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“…The same result was obtained in the present study using a fragment of the mouse OTC promoter region. Furthermore, it was reported that a 1.3-kbp fragment of the rat OTC promoter region is active in a hepatoma cell line (46), and there are two HNF4-binding sites in this promoter region (20). Indeed, there are also two HNF4␣-binding sites in the mouse promoter.…”

Section: Discussionmentioning

confidence: 99%

Defective Ureagenesis in Mice Carrying a Liver-specific Disruption of Hepatocyte Nuclear Factor 4α (HNF4α)

Inoue

Hayhurst

Inoue

et al. 2002

Journal of Biological Chemistry

101

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Hepatocyte nuclear factor 4␣ (HNF4␣) regulates the expression of many genes preferentially expressed in liver. HNF4␣-null mice die during embryogenesis precluding the analysis of its function in the adult. To circumvent this problem, liver-specific HNF4␣-null mice were produced. Mice lacking hepatic HNF4␣ expression exhibited increased serum ammonia and reduced serum urea. This disruption in ureagenesis may be explained by a marked decrease in expression and activity of hepatic ornithine transcarbamylase (OTC). To determine the molecular mechanisms involved in transcriptional regulation of the mouse OTC gene, the OTC promoter region was analyzed. Sequence analysis revealed the presence of two putative HNF4␣-binding sites in the mouse OTC promoter region. By using transient transfection analysis, it was established that high levels of promoter activity were dependent on both HNF4␣-binding sites and the expression of HNF4␣. Furthermore, the proximal HNF4␣-binding site was found to be more important than the distal one for transactivating OTC promoter. These data demonstrate that HNF4␣ is critical for urea homeostasis by direct regulation of the OTC gene in vivo.The liver plays an important role in the metabolism of carbohydrates, proteins, lipids, vitamins, and hormones, the synthesis and excretion of bile acids, the production of blood coagulation factors and plasma proteins, and the detoxification of various xenobiotics. Most of these functions are achieved by hepatocytes that account for over 60% of the liver mass. The expression of genes preferentially expressed in liver is controlled by liver-enriched transcription factors (LETF)

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Promoter and 11-kilobase upstream enhancer elements responsible for hepatoma cell-specific expression of the rat ornithine transcarbamylase gene.

Cited by 48 publications

References 68 publications

Amino Acid Limitation Induces Expression of CHOP, a CCAAT/Enhancer Binding Protein-related Gene, at Both Transcriptional and Post-transcriptional Levels

Amino Acid Limitation Induces Expression of CHOP, a CCAAT/Enhancer Binding Protein-related Gene, at Both Transcriptional and Post-transcriptional Levels

Characterization of a thyroid-specific enhancer located 5.5 kilobase pairs upstream of the human thyroid peroxidase gene.

Defective Ureagenesis in Mice Carrying a Liver-specific Disruption of Hepatocyte Nuclear Factor 4α (HNF4α)

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