| Budget Amount *help |
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1995: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1994: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Research Abstract |
In multi-step tumorigenesis, change in the pattern of gene expression might be an important step, as well as the steps of oncogene activation and/or inactivation of anti-oncogene. To investigate the possible alteration of the cellular pattern of gene expression during neoplastic transformation, it may be useful to explore tumor maker gene as one of the tools. From this view point, we have been studying the regulation mechanism of glutathione transferase P (GST-P) gene during chemical hepatocarcinogenesis of the rat, and obtained following results.
1 Jun and Fos related factors : GST-P gene has multiple TRE-like elements and is activated by Jun and Fos. All of related to these factors bind and modulate the GST-P expression. FosB and dFosB were repressed the GST-P expression.
2 Peroxisome proliferators suppressed the GST-P expression : Peroxisome proliferator activated receptor (PPAR) interacts with Jun and inhibits the GST-P expression. PPAR expression was decreased in the early stages of hepatocarcinogenesis of the rat. This suggests PPAR functions, at least in part, to the derepression of the GST-P gene in early stage of neoplastic transformation.
3 The TRE sequence located on the promoter of the GST-P gene is also binding consensus sequence of the transcription factor Maf. We have obtained the results that indicate the Maf binds to GST-P promoter and activates GST-P gene strongly. However, since the observation that the expression of GST-Pgene and Maf was not correlated during hepatocarcinogenesis, Maf is not the main regulator of GST-P expression in early stages of carcinogenesis. Gel mobility shift analysis using nuclear extracts from the liver bearing hyperplastic nodules and transfection analysis using dominant-negative genes of maf, suggest that some Maf related factor (s) activate GST-P gene.
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