Tissue-specific transcription of the mouse alpha-fetoprotein gene promoter is dependent on HNF-1.

Feuerman, Miriam H.; Godbout, Roseline; Ingram, Robert S.; Tilghman, Shirley M.

doi:10.1128/mcb.9.10.4204

Cited by 126 publications

(90 citation statements)

References 46 publications

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“…About 80% of enhancer stimulation was eliminated by removal of the PCE, but this stimulation also depended on HNF1, as in the albumin promoter. Inactivation of either AFP-promoter HNF1 site reduced activity by about half, whereas inactivation of both totally inactivated transcription (53)(54)(55). The requirement for HNF1 is virtually identical with the heterologous SV40 enhancer.…”

Section: Discussionmentioning

confidence: 99%

Distant Enhancers Stimulate the Albumin Promoter through Complex Proximal Binding Sites

Vorachek

Steppan

Lima

et al. 2000

Journal of Biological Chemistry

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The albumin-␣-fetoprotein locus epitomizes the main features of transcriptional regulation of fetal and adult hepatocyte-specific genes: developmentally regulated promoters and strong distant enhancers. Full enhancer activity required only a proximal albumin-promoter region containing the TATA box, hepatic nuclear factor 1 (HNF1), and nuclear factor Y (NF-Y) sites. Deletion of the HNF1 site abrogated enhancer and promoter activity, whereas methylation of the site reduced all activity by about 3-fold. Deletion of the NF-Y site attenuated activity by about half, but much of the activity could be replaced by juxtaposition of an upstream region (designated distal element IV). Gel shift and competition analysis demonstrated that binding of architectural factors overlapped NF-Y binding. Moreover, a mutation that eliminated NF-Y binding but only minimally perturbed the surrounding region did not affect enhancer function. In plasmids with a second promoter, the enhancers simultaneously stimulated both albumin and ␣-fetoprotein promoters with minimal competition, but surprisingly some mutations in the albumin promoter attenuated expression from both promoters, whereas another uncoupled their expression. With single promoters, the function of the proximal promoter region was controlled by three parameters in the following hierarchy: HNF1 binding > local architecture > NF-Y binding, but integrated two-promoter function had a much greater dependence on NF-Y.

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Section: Discussionmentioning

confidence: 99%

Distant Enhancers Stimulate the Albumin Promoter through Complex Proximal Binding Sites

Vorachek

Steppan

Lima

et al. 2000

Journal of Biological Chemistry

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“…In the enhancers, on the other hand, the AT-rich element is present in the human AFP gene but not in the mouse and rat genes (13). The human AFP enhancer AT motif is also unique in that HNF1 binds to it 10-fold less efficiently than to the bona fide HNF1 site present in the liver-specific promoter (9). These observations suggest that HNF1 may not be the only factor regulating the human AFP enhancer AT motif; however, other proteins may also be involved in its regulation.…”

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confidence: 99%

ATBF1, a multiple-homeodomain zinc finger protein, selectively down-regulates AT-rich elements of the human alpha-fetoprotein gene.

Yasuda¹,

Mizuno²,

Tamaoki³

et al. 1994

Mol. Cell. Biol.

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ATBF1 is a 306-kDa protein containing four homeodomains, 17 zinc finger motifs, and several segments potentially involved in transcriptional regulation (T. Morinaga, H. Yasuda, T. Hashimoto, K. Higashio, and T. Tamaoki, Mol. Cell. Biol. 11:6041-6049, 1991). At least one of the homeodomains of ATBF1 binds to an AT-rich element in the human a-fetoprotein (AFP) enhancer (enhancer AT motif). In the present work, we analyzed the transcriptional regulatory activity of ATBF1 with respect to the enhancer AT motif and similar AT-rich elements in the human AFP promoter and the human albumin promoter and enhancer. Gel retardation assays showed that ATBF1 binds to the AFP enhancer AT motif efficiently; however, it binds weakly or not at all to other AT-rich elements in the AFP and albumin regulatory regions studied. Alterations of the enhancer AT motif by site-specific mutagenesis resulted in the loss of binding of ATBF1. Cotransfection experiments with an ATBF1 expression plasmid and the chloramphenicol acetyltransferase (CAT) gene fused to AFP promoter or enhancer fragments showed that ATBF1 suppressed the activity of AFP enhancer and promoter regions containing AT-rich elements. This suppression was reduced when the mutated AT motifs with low affinity to ATBF1 were linked to the CAT gene. The ATBF1 suppression of AFP promoter and enhancer activities appeared to be due, at least in part, to competition between ATBF1 and HNF1 for the same binding site. In contrast to the AFP promoter and enhancer, the albumin promoter and enhancer were not affected by ATBF1, although they contain homologous AT-rich elements. These results show that ATBF1 is able to distinguish AFP and albumin AT-rich elements, leading to selective suppression of the AFP promoter and enhancer activities.The regulatory regions of all genes so far studied contain multiple cis-acting elements which interact with trans-acting factors (22,32). Liver-specific gene expression is also achieved through a combinatorial action of regulatory DNA elements and interacting transcription factors (20,21,30). One characteristic feature of a number of liver-specific promoters is the presence of DNA sequences having a well-organized array of 10 to 11 adenine (A) and thymine (T) residues sandwiched by a guanine (G) and a cytosine (C) (AT-rich element) (4-7, 11, 15, 23, 26, 40). These elements have been shown to be the binding sites of a liver-enriched transcription factor, HNF1 (also called LF-B1 and APF) (3-6, 12, 31). Mutations of the AT-rich element cause drastic reduction of liver-specific transcriptional activity both in vitro and in vivo (21, 28, 33, 42), indicating that the AT-rich element and HNF1 play a crucial role in liver-specific promoter activation.In the promoters of a-fetoprotein (AFP) genes of mice, rats, and humans, two HNF1-binding sites are conserved. In the enhancers, on the other hand, the AT-rich element is present in the human AFP gene but not in the mouse and rat genes (13). The human AFP enhancer AT motif is also unique in that HNF1 binds to it 10-fold...

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“…23,24 Clinically, AFP elevation in sera or AFP mRNA expression in HCC occurs more often in HCC patients of younger age 9 and positive for serum HBsAg. 10,11 But the molecular mechanism is not fully understood.…”

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confidence: 99%

High α‐fetoprotein level correlates with high stage, early recurrence and poor prognosis of hepatocellular carcinoma: Significance of hepatitis virus infection, age, p53 and β‐catenin mutations

Shu

Chen²,

Lai

et al. 2004

Intl Journal of Cancer

285

219

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Key words: ␣-fetoprotein; hepatocellular carcinoma; p53; ␤-catenin; tumor stage; prognosis ␣-Fetoprotein (AFP), a member of the albuminoid multigene family located at chromosome 4q11-q13, 1 is abundantly expressed in the fetal yolk sac and liver, 2,3 but not in normal adult tissues. Chromosome 4q is one of the most frequent chromosomal region exhibiting allelic losses in hepatocellular carcinoma (HCC), 4 -7 whereas AFP expression resurges during liver regeneration 8 and in HCC. 2,8 -10 The AFP elevation in HCC has been shown to correlate with poor tumor differentiation, 9,10 tumor burden, 11 early recurrence after tumor resection 12,13 and unfavorable prognosis. 11 Serum AFP elevation concurrent with aberrant growth is usually regarded as coincidental, and its role in HCC progression receives little attention. However, cumulative evidence has shown that AFP plays an important role in the regulation of tumor growth and cell differentiation 14 -17 and can stimulate proliferation of human hepatoma cells, probably through the AFP receptors. 17-19 AFP-producing gastric cancer is more aggressive with higher malignant potential, high frequency of liver metastasis and a poor prognosis than AFP-negative gastric cancers. 20,21 HCC clones derived from the same parent cell line exhibited higher serum AFP levels in nude mice bearing tumor implants with high metastatic potential than in those with low metastatic tumor implants. 22 These findings indicate the potential role of AFP in progression and metastasis of HCC.Regulation of AFP gene expression is a complex process mediated by a number of transcriptional activators and repressors binding to a complex of promoter and enhancer(s) within the AFP gene. 23,24 Clinically, AFP elevation in sera or AFP mRNA expression in HCC occurs more often in HCC patients of younger age 9 and positive for serum HBsAg. 10,11 But the molecular mechanism is not fully understood. The tumor suppressor p53 acts through its binding within the AFP repressor region, displacing bound HNF-3 and altering the chromatin structure at the core promoter, to repress AFP gene expression. 25,26 Recently, it is shown that mutant ␤-catenin can induce p53 expression via the induction of p14(ARF), 27 which in turn leads to suppression of AFP expression through site-specific DNA binding within the AFP repressor domain, and the repression is abolished by mutation within the DNA binding domain of p53 protein. 25 The p53 and ␤-catenin genes are the 2 most commonly mutated genes in HCC, 28 -33 but their potential interplay in AFP elevation remains to be elucidated.In this study, we aimed to examine the AFP levels in HCC with special emphases on their relations to the tumor progression, the related factors including mutations of p53 and ␤-catenin and the usefulness of AFP mRNA detection in the liver for the prediction of early tumor recurrence. MATERIAL AND METHODS PatientsFrom 1987 to 1997, 909 surgically resected primary HCCs were pathologically assessed at the National Taiwan University Hospital. Among them, 781 unif...

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Tissue-specific transcription of the mouse alpha-fetoprotein gene promoter is dependent on HNF-1.

Cited by 126 publications

References 46 publications

Distant Enhancers Stimulate the Albumin Promoter through Complex Proximal Binding Sites

Distant Enhancers Stimulate the Albumin Promoter through Complex Proximal Binding Sites

ATBF1, a multiple-homeodomain zinc finger protein, selectively down-regulates AT-rich elements of the human alpha-fetoprotein gene.

High α‐fetoprotein level correlates with high stage, early recurrence and poor prognosis of hepatocellular carcinoma: Significance of hepatitis virus infection, age, p53 and β‐catenin mutations

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