Mini ReviewRegulation of glutathione transferase P: A tumor marker of hepatocarcinogenesis
Section snippets
Expression of the GST-P gene during hepatocarcinogenesis
Specific expression of GST-P in the pre-neoplastic lesion was first identified by the proteomic analyses of rat liver bearing hyperplastic nodules, which were induced by experimental hepatocarcinogenesis [18], [11]. GST-P in the rat is markedly induced in pre-neoplastic foci and nodules, and is detected in a single cell as early as 2–3 days after the administration of the chemical carcinogen. This gene is expressed in response to almost all of the chemical carcinogens, with the rare exception
Structure and functional elements of the GST-P gene
The GST-P gene is composed of 7 exons and the typical promoter sequence containing TATA- and GC-boxes. ARE/TRE (antioxidant responsive element/phorbol 12-o-tetradecanoate 13-acetate (TPA) responsive element) is located at −61 bp. A strong enhancer element, GST-P enhancer-1 (GPE1) is located −2.5 kb upstream from the cap site. The GPE1 consists of two TRE-like sequences with palindromic orientation (5′-TCAGTCAGTCACTATGATTCAGCAA-3′, TRE-Like sequences are underlined) [14]. These TRE sequences are
Nrf2/MafK heterodimer is an activator for the GPE1 enhancer
We identified a heterodimer of Nrf2 (NF-E2 p45-related factor 2) and MafK as the transcription factor that binds and activates the GPE1 enhancer in hepatocarcinogenesis [3]. Nrf2 is a member of the CNC (cap’n’ collar) family of transcription factors, which dimerizes with small Maf proteins such as MafK, MafG, and MafF. The Nrf2/MafK heterodimer binds to ARE (antioxidant responsive element) and MARE (Maf recognition element) and regulates the genes containing these elements including those of
CAAT enhancer binding protein (C/EBP) α represses GST-P gene expression in the normal liver
Interaction of Nrf2/MafK with the GPE1 enhancer positively regulates the expression of the GST-P gene during hepatocarcinogenesis. However, some findings suggest that GPE1 may negatively regulate the expression of the GST-P gene in normal liver. In transgenic rats, the transgene that contained GPE1 element was not expressed in normal liver cells. In the mouse, GST-P1 (homologue of rat GST-P) gene lacked a GPE1 or related element and was significantly expressed in normal liver cells. This
Modification of the chromatin of the GST-P gene
Acetylation of the histones H3 and H4 in the GPE1 and promoter regions of the GST-P gene was investigated by ChIP analyses. As shown in Fig. 1B, histones H3 and H4 were not acetylated in either the GPE1 or the promoter regions in normal liver cells. In contrast, both histones H3 and H4 were heavily acetylated in the GPE1 and in the promoter regions of the GST-P gene in hepatoma cells, and the acetylation of histones was correlated with the activation of the GST-P gene [3]. Recently, we found
Discussion
The fundamental pathway for the specific regulation of GST-P gene in normal liver and during hepatocarcinogenesis is now elucidated. The positive and negative regulation of this gene occurs primarily at the transcriptional level and requires the enhancer element GPE1 (Fig. 2). In the normal liver, C/EBPα binds to the GPE1 element and silences the GST-P gene. After administration of carcinogen, C/EBPα expression is down regulated and substituted by heterodimer Nrf2/MafK in the pre-neoplastic
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