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Expression of the human glucokinase gene: important roles of the 5' flanking and intron 1 sequences.


ABSTRACT:

Background

Glucokinase plays important tissue-specific roles in human physiology, where it acts as a sensor of blood glucose levels in the pancreas, and a few other cells of the gut and brain, and as the rate-limiting step in glucose metabolism in the liver. Liver-specific expression is driven by one of the two tissue-specific promoters, and has an absolute requirement for insulin. The sequences that mediate regulation by insulin are incompletely understood.

Methodology/principal findings

To better understand the liver-specific expression of the human glucokinase gene we compared the structures of this gene from diverse mammals. Much of the sequence located between the 5' pancreatic beta-cell-specific and downstream liver-specific promoters of the glucokinase genes is composed of repetitive DNA elements that were inserted in parallel on different mammalian lineages. The transcriptional activity of the liver-specific promoter 5' flanking sequences were tested with and without downstream intronic sequences in two human liver cells lines, HepG2 and L-02. While glucokinase liver-specific 5' flanking sequences support expression in liver cell lines, a sequence located about 2000 bases 3' to the liver-specific mRNA start site represses gene expression. Enhanced reporter gene expression was observed in both cell lines when cells were treated with fetal calf serum, but only in the L-02 cells was expression enhanced by insulin.

Conclusions/significance

Our results suggest that the normal liver L-02 cell line may be a better model to understand the regulation of the liver-specific expression of the human glucokinase gene. Our results also suggest that sequences downstream of the liver-specific mRNA start site have important roles in the regulation of liver-specific glucokinase gene expression.

SUBMITTER: Wang Y 

PROVIDER: S-EPMC3447760 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Expression of the human glucokinase gene: important roles of the 5' flanking and intron 1 sequences.

Wang Yi Y   Guo Tingting T   Zhao Shuyong S   Li Zhixin Z   Mao Yiqing Y   Li Hui H   Wang Xi X   Wang Rong R   Xu Wei W   Song Rongjing R   Jin Ling L   Li Xiuli X   Irwin David M DM   Niu Gang G   Tan Huanran H  

PloS one 20120920 9


<h4>Background</h4>Glucokinase plays important tissue-specific roles in human physiology, where it acts as a sensor of blood glucose levels in the pancreas, and a few other cells of the gut and brain, and as the rate-limiting step in glucose metabolism in the liver. Liver-specific expression is driven by one of the two tissue-specific promoters, and has an absolute requirement for insulin. The sequences that mediate regulation by insulin are incompletely understood.<h4>Methodology/principal find  ...[more]

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