Hormonal regulation of α1 foetoprotein

Bélanger, Luc; Hamel, D; Lachance, Leo E.; Dufour, Delphine; Tremblay, Mélanie; Gagnon, Philippe

doi:10.1038/256657a0

Cited by 94 publications

(39 citation statements)

References 3 publications

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“…Such findings include hormones such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid hormones, and growth factors. Previous studies showed that AFP was indeed subject to hormonal, nutritional, and hematological regulation (Belanger, 1975). These reports indicated that prednisolone, adrenaline, and thyroxine depressed AFP through a selective blockade of its synthesis.…”

Section: G) Afp Peptide Sites For Hormones and Growth Factor Bindingmentioning

confidence: 93%

Mapping of Structure-Function Peptide Sites on the Human Alpha-fetoprotein Amino Acid Sequence

Mizejewski¹

2011

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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The structure of alpha-fetoprotein (AFP) is presen-ted in light of AFP membership and position in the albuminoid gene family in comparison to other gene family members. Ontogenetic AFP gene expression is reviewed considering AFP mRNA presence in various tissues at different times during development. The multiple molecular variant forms of AFP are discussed in relation to published reports of AFP binding proteins and cell surface receptors. The atlas further shows AFP as a protein consisting of multiple peptide-cassettes consisting of amino acid (AA) sequence stretches matched to peptide segments on prohormones and biological response modifier proteins. Such AFP peptide segments could potentially serve as delivery agents which could target vascular, neuroendocrine, or gastrointestinal cells. A discussion follows in which peptide epitopes, extracellular matrix proteins, serine proteases, extracellular matrix, and cellular adhesion AA identity sites on AFP are considered. The AFP molecule is also viewed as a carrier/ transport protein based on AA sequence comparison of various proteins that bind hydropho-bic ligands and heavy metals similar to AFP binding of such components. An analysis of trans-cription factors, tumor suppressors, and AA-rich motifs follows, interfaced with dimerization and nuclear localization sequence matches identified on the AFP molecule. Emphasis is further placed upon homeodomain and apoptosis AA sequence identi-ties given that AFP serves as a fetal, phasespecific protein throughout embryogenesis, histogenesis, and organogenesis. AFP AA sequences are further presented as peptide identification sites for Mapping of Structure-Function Peptide Sites on the Human Alpha-fetoprotein Amino Acid SequenceMizejewski GJ Atlas Genet Cytogenet Oncol Haematol. 2010; 14(2) 170 growth factors, receptors, cytoskeletal proteins, and chemo-kines. A closing discussion summarizes the multi-ple and varied motifs of peptide sequences matched to AAs on each of AFP's three domains. This study indicates that short peptide segments, in addition to full-length AFP, and domain and subdomain fragments of AFP, could be employed as functional agents to help unravel the complexity of biological roles ascribed to human AFP.

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Section: G) Afp Peptide Sites For Hormones and Growth Factor Bindingmentioning

confidence: 93%

Mapping of Structure-Function Peptide Sites on the Human Alpha-fetoprotein Amino Acid Sequence

Mizejewski¹

2011

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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“…Thus, as FTF initiates hepatic functions at the AFP promoter, it would also enhance other transcription factors engaged into liver-induction networks. We recall here that AFP gene activity is restricted to early proliferative stages of liver development and that the FTF regulation domain in the AFP promoter is deactivated by hormonal signals that interrupt liver cell growth (9,11,44); this implies that the FTF function may be dependent upon or enhanced by cell growth stimuli. Although other potential FTF liver gene targets have recently been proposed (21,29,31,45,46), it is uncertain whether all FTF effects can actually proceed in nongrowing hepatocytes since most results were obtained by cotransfection in growing cultured cells.…”

Section: Ftf Gene Structure and Splicementioning

confidence: 99%

The Mouse Fetoprotein Transcription Factor (FTF) Gene Promoter Is Regulated by Three GATA Elements with Tandem E Box and Nkx Motifs, and FTF in Turn Activates the Hnf3β, Hnf4α, and Hnf1α Gene Promoters

Paré

Roy

Galarneau

et al. 2001

Journal of Biological Chemistry

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Fetoprotein transcription factor (FTF) is an orphan nuclear receptor that activates the ␣ 1 -fetoprotein gene during early liver developmental growth. Here we sought to define better the position of FTF in transcriptional cascades leading to hepatic differentiation. The mouse FTF gene was isolated and assigned to chromosome 1 band E4 (one mFTF pseudogene was also found). Exon/intron mapping shows an mFTF gene structure similar to that of its close homologue SF1, with two more N-terminal exons in the mFTF gene; exon mapping also delimits several FTF mRNA 5-and 3-splice variants. The mFTF transcription initiation site was located in adult liver at 238 nucleotides from the first translation initiator codon, with six canonical GATA, E box, and Nkx motifs clustered between ؊50/؊140 base pairs (bp) from the cap site; DNA/protein binding assays also pinpointed an HNF4-binding element at ؉36 bp and an FTFbinding element at ؊257 bp. Transfection assays and point mutations showed that the mFTF promoter is activated by GATA, HNF4␣, FTF, Nkx, and basic helixloop-helix factors, with marked cooperativity between GATA and HNF4␣. A tandem GATA/E box activatory motif in the proximal mFTF promoter is strikingly similar to a composite motif coactivated by differentiation inducers in the hematopoietic lineage; a tandem GATANkx motif in the distal mFTF promoter is also similar to a composite motif transducing differentiation signals from transforming growth factor-␤-like receptors in the cardiogenic lineage. Three genes encoding transcription factors critical to early hepatic differentiation, Hnf3␤, Hnf4␣, and Hnf1␣, each contain dual FTF-binding elements in their proximal promoters, and all three promoters are activated by FTF in transfection assays. Direct DNA binding action and cooperativity was demonstrated between FTF and HNF3␤ on the Hnf3␤ promoter and between FTF and HNF4␣ on the Hnf1␣ promoter. These combined results suggest that FTF is an early intermediary between endodermal specification signals and downstream genes that establish and amplify the hepatic phenotype.At 8 -8.5 days of mouse embryogenesis, endodermal cells of the ventral foregut interact with the cardiac mesoderm and become committed to the hepatic differentiation program; these newly specified cells then migrate and proliferate in the mesenchyme of the septum transversum where liver morphogenesis becomes apparent at ϷE10.5 (1, 2). Initial induction of hepatic functions is driven in part by growth factors of the FGF 1 family, secreted by cardiac mesodermal cells and acting via transmembrane receptor kinases at the endodermal cell surface (3). The process also involves potentiating transcription factors among which GATA factors appear essential to endodermal determination across vertebrates as well as invertebrates (Ref. 4 and references therein). Following liver specification, transcriptional activation cascades further develop among early hepatic transcription factors creating interactive regulatory networks that amplify the induction signals and imprint the...

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“…A part of these functions is accomplished by nutrient carrier proteins of the albumin gene family, a multigene locus expressed by the liver and subject to precise developmental controls. One albumin-related gene, the ␣ 1 -fetoprotein (AFP) 1 gene, is activated at the onset of liver differentiation and operates tightly coupled with liver growth (2,3). In 1988, our group circumscribed a proximal AFP promoter element essential to AFP gene activity in hepatocytes, and distinct from promoter components regulating the other albumin loci (4).…”

mentioning

confidence: 99%

The Fetoprotein Transcription Factor (FTF) Gene Is Essential to Embryogenesis and Cholesterol Homeostasis and Is Regulated by a DR4 Element

Paré

Malenfant

Courtemanche

et al. 2004

Journal of Biological Chemistry

145

134

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Development of the mammalian embryo relies upon nutritive functions fulfilled by the visceral endoderm and then by the liver (1). A part of these functions is accomplished by nutrient carrier proteins of the albumin gene family, a multigene locus expressed by the liver and subject to precise developmental controls. One albumin-related gene, the ␣ 1 -fetoprotein (AFP) 1 gene, is activated at the onset of liver differentiation and operates tightly coupled with liver growth (2, 3). In 1988, our group circumscribed a proximal AFP promoter element essential to AFP gene activity in hepatocytes, and distinct from promoter components regulating the other albumin loci (4). The AFP-specific activator was then identified as orphan receptor fetoprotein transcription factor (5-7), so named for its first identified target locus (genome data base nomenclature, 2 NR5A2 in the nuclear receptor nomenclature, Ref. 9); also referred to as LRH1 or CPF). FTF belonged to a primitive class of nuclear receptors and emerged as a critical lead to connect AFP gene activation with early embryonic growth and differentiation processes.Subsequent studies indicated that developmental FTF functions even preceded its activation of the AFP locus in hepatocytes. In situ hybridization analysis in the mouse at embryonic day 8 -9 showed abundant FTF transcripts in the foregut endoderm, before liver morphogenesis (10). Characterization of the FTF gene promoter also revealed a cluster of regulatory motifs conserved in distant species and potential targets of cell lineage specification factors (11). Among these were three proximal binding sites for GATA factors, known to be essential for visceral endoderm function (12, 13). Furthermore, three HNF genes important to liver differentiation, HNF1␣, HNF4␣, and HNF3␤, were found to each contain double FTF-binding sites in their proximal promoter and to be activated by FTF in transfection assays (11). Thus, a pivotal role was suggested for FTF in a transcriptional cascade using determination factors to activate FTF in prehepatic endodermal cells, and then using FTF to drive AFP and other effectors of the hepatic program.

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Hormonal regulation of α1 foetoprotein

Cited by 94 publications

References 3 publications

Mapping of Structure-Function Peptide Sites on the Human Alpha-fetoprotein Amino Acid Sequence

Mapping of Structure-Function Peptide Sites on the Human Alpha-fetoprotein Amino Acid Sequence

The Mouse Fetoprotein Transcription Factor (FTF) Gene Promoter Is Regulated by Three GATA Elements with Tandem E Box and Nkx Motifs, and FTF in Turn Activates the Hnf3β, Hnf4α, and Hnf1α Gene Promoters

The Fetoprotein Transcription Factor (FTF) Gene Is Essential to Embryogenesis and Cholesterol Homeostasis and Is Regulated by a DR4 Element

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