Bulla G A
Pediatric Research Institute, St Louis University Health Sciences Center and Cardinal Glennon Children's Hospital, 3662 Park Avenue, St Louis, MO 63110, USA.
Nucleic Acids Res. 1997 Jun 15;25(12):2501-8. doi: 10.1093/nar/25.12.2501.
Hepatocyte nuclear factors-1alpha (HNF1alpha) and -4 (HNF4) are components of a liver-enriched transcription activation pathway which is thought to play a critical role in hepatocyte-specific gene expression, including activation of alpha1-antitrypsin gene expression. HNF1alpha, HNF4 and alpha1-antitrypsin (alpha1AT) genes are extinguished in hepatoma/fibroblast somatic cell hybrids, suggesting that fibroblasts contain a repressor-like activity. To determine the molecular basis for silencing of these genes in cell hybrids, ectopic expression of HNF1alpha and HNF4 was used. Results show that constitutive expression of HNF4 prevents extinction of HNF1alpha gene expression in hepatoma/fibroblast hybrids. In contrast, forced HNF1alpha expression failed to prevent extinction of the HNF4 locus in cell hybrids. Likewise, the alpha1AT gene remained silent in the presence of both HNF1alpha and HNF4. These results suggest that extinction of HNF1alpha is a simple lack-of-activation phenotype, whereas extinction of HNF4 andalpha1AT loci is more complex, perhaps involving negative regulation.
肝细胞核因子-1α（HNF1α）和-4（HNF4）是肝脏富集转录激活途径的组成部分，该途径被认为在肝细胞特异性基因表达中起关键作用，包括α1-抗胰蛋白酶基因表达的激活。HNF1α、HNF4和α1-抗胰蛋白酶（α1AT）基因在肝癌/成纤维细胞体细胞杂种中被抑制，这表明成纤维细胞含有一种类似阻遏物的活性。为了确定这些基因在细胞杂种中沉默的分子基础，采用了HNF1α和HNF4的异位表达。结果表明，HNF4的组成型表达可防止肝癌/成纤维细胞杂种中HNF1α基因表达的抑制。相反，强制表达HNF1α未能阻止细胞杂种中HNF4基因座的抑制。同样，在同时存在HNF1α和HNF4的情况下，α1AT基因仍然沉默。这些结果表明，HNF1α的抑制是一种简单的缺乏激活的表型，而HNF4和α1AT基因座的抑制则更为复杂，可能涉及负调控。
