Transcription factor that is thought to act as a 'pioneer' factor opening the compacted chromatin for other proteins through interactions with nucleosomal core histones and thereby replacing linker histones at target enhancer and/or promoter sites (By similarity). Originally described as a transcription activator for a number of liver genes such as AFP, albumin, tyrosine aminotransferase, PEPCK, etc. Interacts with the cis-acting regulatory regions of these genes. Involved in glucose homeostasis; binds to and activates transcription from the G6PC promoter. Binds to the CYP3A4 promoter and activates its transcription in cooperation with CEBPA. Binds to the CYP3A7 promoter together with members of the CTF/NF-I family. Involved in regulation of neuronal-specific transcription. May be involved in regulation of spermatogenesis.
Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of more than 50% of currently used therapeutic drugs, yet the mechanisms that control CYP3A4 basal expression in liver are poorly understood. Several putative binding sites for CCAAT/enhancer-binding protein (C/EBP) and hepatic nuclear factor 3 (HNF-3) were found by computer analysis in CYP3A4 promoter. The use of reporter gene assays, electrophoretic mobility shift assays, and site-directed mutagenesis revealed that one proximal and two distal C/EBP alpha binding sites are essential sites for the trans-activation of CYP3A4 promoter. No trans-activation was found in similar reporter gene experiments with a HNF-3 gamma expression vector. The relevance of these findings was further explored in the more complex DNA/chromatin structure within endogenous CYP3A4 gene. Using appropriate adenoviral expression vectors, we found that both hepatic and nonhepatic cells overexpressing C/EBP alpha had increased CYP3A4 mRNA levels, but no effect was observed when HNF-3 gamma was overexpressed. In contrast, overexpression of HNF-3 gamma simultaneously with C/EBP alpha resulted in a greater activation of the CYP3A4 gene. This cooperative effect was hepatic-specific and also occurred in CYP3A5 and CYP3A7 genes. To investigate the mechanism for HNF-3 gamma action, we studied its binding to CYP3A4 promoter and the effect of the deacetylase inhibitor trichostatin A. HNF-3 gamma was able to bind CYP3A4 promoter at a distal position, near the most distal C/EBP alpha binding site. Trichostatin A increased C/EBP alpha effect but abolished HNF-3 gamma cooperative action. These findings revealed that C/EBP alpha and HNF-3 gamma cooperatively regulate CYP3A4 expression in hepatic cells by a mechanism that probably involves chromatin remodeling.
The activity of binding selectively and non-covalently to and distorting the original structure of DNA, typically a straight helix, into a bend, or increasing the bend if the original structure was intrinsically bent due to its sequence.
Interacting selectively and non-covalently with a specific domain of a protein.
IBARefGenome
RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activitydefinition[GO:0003705]‹silver
Interacting selectively and non-covalently with a sequence of DNA that is in a distal enhancer region for RNA polymerase II (RNAP II) in order to modulate transcription by RNAP II.
Interacting selectively and non-covalently with DNA of a specific nucleotide composition, e.g. GC-rich DNA binding, or with a specific sequence motif or type of DNA e.g. promotor binding or rDNA binding.
Interacting selectively and non-covalently with a specific DNA sequence in order to modulate transcription. The transcription factor may or may not also interact selectively with a protein or macromolecular complex.
Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of more than 50% of currently used therapeutic drugs, yet the mechanisms that control CYP3A4 basal expression in liver are poorly understood. Several putative binding sites for CCAAT/enhancer-binding protein (C/EBP) and hepatic nuclear factor 3 (HNF-3) were found by computer analysis in CYP3A4 promoter. The use of reporter gene assays, electrophoretic mobility shift assays, and site-directed mutagenesis revealed that one proximal and two distal C/EBP alpha binding sites are essential sites for the trans-activation of CYP3A4 promoter. No trans-activation was found in similar reporter gene experiments with a HNF-3 gamma expression vector. The relevance of these findings was further explored in the more complex DNA/chromatin structure within endogenous CYP3A4 gene. Using appropriate adenoviral expression vectors, we found that both hepatic and nonhepatic cells overexpressing C/EBP alpha had increased CYP3A4 mRNA levels, but no effect was observed when HNF-3 gamma was overexpressed. In contrast, overexpression of HNF-3 gamma simultaneously with C/EBP alpha resulted in a greater activation of the CYP3A4 gene. This cooperative effect was hepatic-specific and also occurred in CYP3A5 and CYP3A7 genes. To investigate the mechanism for HNF-3 gamma action, we studied its binding to CYP3A4 promoter and the effect of the deacetylase inhibitor trichostatin A. HNF-3 gamma was able to bind CYP3A4 promoter at a distal position, near the most distal C/EBP alpha binding site. Trichostatin A increased C/EBP alpha effect but abolished HNF-3 gamma cooperative action. These findings revealed that C/EBP alpha and HNF-3 gamma cooperatively regulate CYP3A4 expression in hepatic cells by a mechanism that probably involves chromatin remodeling.
The gene for glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis, is expressed in a tissue-specific manner in the liver and kidney. To understand the molecular mechanisms regulating liver-specific expression of the G6Pase gene, we characterized G6Pase promoter activity by transient expression assays. The G6Pase promoter is active in HepG2 hepatoma cells, but inactive in JEG3 choriocarcinoma or 3T3 cells. DNA elements essential for optimal and liver-specific expression of the G6Pase gene were contained within nucleotides -234 to +3. Deletion analysis revealed that the G6Pase promoter contained three activation elements (AEs) at nucleotides -234 to -212 (AE-I), -146 to -125 (AE-II), and -124 to -71 (AE-III). AE-I contains binding sites for hepatocyte nuclear factors (HNF) 1 and 4. Electromobility shift and cotransfection assays demonstrated that HNF1alpha, but not HNF4, bound to its cognate site and transactivated G6Pase gene expression. The G6Pase promoter contained five HNF3 motifs, 1 (-180/-174), 2 (-139/-133), 3 (-91/-85), 4 (-81/-75), and 5 (-72/-66), and all five sites bound HNF3gamma with high affinity. Transient expression and cotransfection assays showed that HNF3 site 1 is not required for basal promoter activity, but is essential for HNF3gamma-activated transcription from the G6Pase promoter. We further showed that HNF3 sites 3, 4, and 5 were essential for basal G6Pase promoter activity and transactivation by HNF3gamma. AE-II contains, in addition to a HNF3 motif, a cAMP-response element (CRE) and a C/EBP half-site. The G6Pase(-146/-116) DNA containing AE-II formed multiple protein-DNA complexes with HepG2 nuclear extracts, including HNF3gamma, CRE-binding protein (CREB), C/EBPalpha, and C/EBPbeta. We showed that AE-II mediated transcription activation of the G6Pase gene by cAMP.
Interacting selectively and non-covalently with a DNA region that regulates the transcription of a region of DNA, which may be a gene, cistron, or operon. Binding may occur as a sequence specific interaction or as an interaction observed only once a factor has been recruited to the DNA by other factors.
Evidence
1:
Inferred from Mutant PhenotypeUniProtKB
The transcription factor (TF) Foxp2 has been shown to partially repress surfactant protein C (SP-C) transcription, presumably through interaction of an independent repressor domain with a conserved Foxp2 consensus site in the SP-C promoter. We explored the role of interactions between Foxp2 and the homeodomain TF Nkx2.1 that may contribute to the marked reduction in SP-C expression accompanying phenotypic transition of alveolar epithelial type II (AT2) to type I (AT1) cells. Foxp2 dose-dependently inhibited Nkx2.1-mediated activation of SP-C in MLE-15 cells. While electrophoretic mobility shift assays and chromatin immunoprecipitations revealed an interaction between Foxp2 and the conserved consensus motif in the SP-C promoter, Nkx2.1-mediated activation of the 318-bp proximal SP-C promoter (which lacks a Foxp2 consensus) was attenuated by increasing amounts of Foxp2. Co-immunoprecipitation and mammalian two-hybrid assays confirmed a physical interaction between Nkx2.1 and Foxp2 mediated through the Nkx2.1 homeodomain. Formation of an Nkx2.1 complex with an SP-C oligonucleotide was inhibited dose-dependently by recombinant Foxp2. These findings demonstrate that direct interaction between Foxp2 and Nkx2.1 inhibits Nkx2.1 DNA-binding and transcriptional activity and suggest a mechanism for down-regulation of SP-C (and probably other AT2 cell genes) during transition of AT2 cells to an AT1 cell phenotype.
Evidence
2:
Inferred from Mutant PhenotypeUniProtKB
Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of more than 50% of currently used therapeutic drugs, yet the mechanisms that control CYP3A4 basal expression in liver are poorly understood. Several putative binding sites for CCAAT/enhancer-binding protein (C/EBP) and hepatic nuclear factor 3 (HNF-3) were found by computer analysis in CYP3A4 promoter. The use of reporter gene assays, electrophoretic mobility shift assays, and site-directed mutagenesis revealed that one proximal and two distal C/EBP alpha binding sites are essential sites for the trans-activation of CYP3A4 promoter. No trans-activation was found in similar reporter gene experiments with a HNF-3 gamma expression vector. The relevance of these findings was further explored in the more complex DNA/chromatin structure within endogenous CYP3A4 gene. Using appropriate adenoviral expression vectors, we found that both hepatic and nonhepatic cells overexpressing C/EBP alpha had increased CYP3A4 mRNA levels, but no effect was observed when HNF-3 gamma was overexpressed. In contrast, overexpression of HNF-3 gamma simultaneously with C/EBP alpha resulted in a greater activation of the CYP3A4 gene. This cooperative effect was hepatic-specific and also occurred in CYP3A5 and CYP3A7 genes. To investigate the mechanism for HNF-3 gamma action, we studied its binding to CYP3A4 promoter and the effect of the deacetylase inhibitor trichostatin A. HNF-3 gamma was able to bind CYP3A4 promoter at a distal position, near the most distal C/EBP alpha binding site. Trichostatin A increased C/EBP alpha effect but abolished HNF-3 gamma cooperative action. These findings revealed that C/EBP alpha and HNF-3 gamma cooperatively regulate CYP3A4 expression in hepatic cells by a mechanism that probably involves chromatin remodeling.
Evidence
3:
Inferred from Mutant PhenotypeUniProtKB
The gene for glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis, is expressed in a tissue-specific manner in the liver and kidney. To understand the molecular mechanisms regulating liver-specific expression of the G6Pase gene, we characterized G6Pase promoter activity by transient expression assays. The G6Pase promoter is active in HepG2 hepatoma cells, but inactive in JEG3 choriocarcinoma or 3T3 cells. DNA elements essential for optimal and liver-specific expression of the G6Pase gene were contained within nucleotides -234 to +3. Deletion analysis revealed that the G6Pase promoter contained three activation elements (AEs) at nucleotides -234 to -212 (AE-I), -146 to -125 (AE-II), and -124 to -71 (AE-III). AE-I contains binding sites for hepatocyte nuclear factors (HNF) 1 and 4. Electromobility shift and cotransfection assays demonstrated that HNF1alpha, but not HNF4, bound to its cognate site and transactivated G6Pase gene expression. The G6Pase promoter contained five HNF3 motifs, 1 (-180/-174), 2 (-139/-133), 3 (-91/-85), 4 (-81/-75), and 5 (-72/-66), and all five sites bound HNF3gamma with high affinity. Transient expression and cotransfection assays showed that HNF3 site 1 is not required for basal promoter activity, but is essential for HNF3gamma-activated transcription from the G6Pase promoter. We further showed that HNF3 sites 3, 4, and 5 were essential for basal G6Pase promoter activity and transactivation by HNF3gamma. AE-II contains, in addition to a HNF3 motif, a cAMP-response element (CRE) and a C/EBP half-site. The G6Pase(-146/-116) DNA containing AE-II formed multiple protein-DNA complexes with HepG2 nuclear extracts, including HNF3gamma, CRE-binding protein (CREB), C/EBPalpha, and C/EBPbeta. We showed that AE-II mediated transcription activation of the G6Pase gene by cAMP.
The process whose specific outcome is the progression of the brain over time, from its formation to the mature structure. Brain development begins with patterning events in the neural tube and ends with the mature structure that is the center of thought and emotion. The brain is responsible for the coordination and control of bodily activities and the interpretation of information from the senses (sight, hearing, smell, etc.).
A cellular homeostatic process involved in the maintenance of an internal steady state of glucose within a cell or between a cell and its external environment.
The gene for glucose-6-phosphatase (G6Pase), the key enzyme in glucose homeostasis, is expressed in a tissue-specific manner in the liver and kidney. To understand the molecular mechanisms regulating liver-specific expression of the G6Pase gene, we characterized G6Pase promoter activity by transient expression assays. The G6Pase promoter is active in HepG2 hepatoma cells, but inactive in JEG3 choriocarcinoma or 3T3 cells. DNA elements essential for optimal and liver-specific expression of the G6Pase gene were contained within nucleotides -234 to +3. Deletion analysis revealed that the G6Pase promoter contained three activation elements (AEs) at nucleotides -234 to -212 (AE-I), -146 to -125 (AE-II), and -124 to -71 (AE-III). AE-I contains binding sites for hepatocyte nuclear factors (HNF) 1 and 4. Electromobility shift and cotransfection assays demonstrated that HNF1alpha, but not HNF4, bound to its cognate site and transactivated G6Pase gene expression. The G6Pase promoter contained five HNF3 motifs, 1 (-180/-174), 2 (-139/-133), 3 (-91/-85), 4 (-81/-75), and 5 (-72/-66), and all five sites bound HNF3gamma with high affinity. Transient expression and cotransfection assays showed that HNF3 site 1 is not required for basal promoter activity, but is essential for HNF3gamma-activated transcription from the G6Pase promoter. We further showed that HNF3 sites 3, 4, and 5 were essential for basal G6Pase promoter activity and transactivation by HNF3gamma. AE-II contains, in addition to a HNF3 motif, a cAMP-response element (CRE) and a C/EBP half-site. The G6Pase(-146/-116) DNA containing AE-II formed multiple protein-DNA complexes with HepG2 nuclear extracts, including HNF3gamma, CRE-binding protein (CREB), C/EBPalpha, and C/EBPbeta. We showed that AE-II mediated transcription activation of the G6Pase gene by cAMP.
Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of deprivation of nourishment.
The process whose specific outcome is the progression of an embryo from its formation until the end of its embryonic life stage. The end of the embryonic stage is organism-specific. For example, for mammals, the process would begin with zygote formation and end with birth. For insects, the process would begin at zygote formation and end with larval hatching. For plant zygotic embryos, this would be from zygote formation to the end of seed dormancy. For plant vegetative embryos, this would be from the initial determination of the cell or group of cells to form an embryo until the point when the embryo becomes independent of the parent plant.
IBARefGenome
Not
Epithelial tube branching involved in lung morphogenesisdefinition[GO:0060441]‹silver
The process in which a highly ordered sequence of patterning events generates the branched epithelial tubes of the lung, consisting of reiterated combinations of bud outgrowth, elongation, and dichotomous subdivision of terminal units.
The process in which a relatively unspecialized cell acquires specialized features of an epithelial cell that contributes to the epithelium of the lung.
The process that regulates the coordinated growth and differentiation that establishes the non-random anterior-posterior spatial arrangement of the neural plate.
The process in which a cell becomes capable of differentiating autonomously into a neuron in an environment that is neutral with respect to the developmental pathway. Upon specification, the cell fate can be reversed.
Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of more than 50% of currently used therapeutic drugs, yet the mechanisms that control CYP3A4 basal expression in liver are poorly understood. Several putative binding sites for CCAAT/enhancer-binding protein (C/EBP) and hepatic nuclear factor 3 (HNF-3) were found by computer analysis in CYP3A4 promoter. The use of reporter gene assays, electrophoretic mobility shift assays, and site-directed mutagenesis revealed that one proximal and two distal C/EBP alpha binding sites are essential sites for the trans-activation of CYP3A4 promoter. No trans-activation was found in similar reporter gene experiments with a HNF-3 gamma expression vector. The relevance of these findings was further explored in the more complex DNA/chromatin structure within endogenous CYP3A4 gene. Using appropriate adenoviral expression vectors, we found that both hepatic and nonhepatic cells overexpressing C/EBP alpha had increased CYP3A4 mRNA levels, but no effect was observed when HNF-3 gamma was overexpressed. In contrast, overexpression of HNF-3 gamma simultaneously with C/EBP alpha resulted in a greater activation of the CYP3A4 gene. This cooperative effect was hepatic-specific and also occurred in CYP3A5 and CYP3A7 genes. To investigate the mechanism for HNF-3 gamma action, we studied its binding to CYP3A4 promoter and the effect of the deacetylase inhibitor trichostatin A. HNF-3 gamma was able to bind CYP3A4 promoter at a distal position, near the most distal C/EBP alpha binding site. Trichostatin A increased C/EBP alpha effect but abolished HNF-3 gamma cooperative action. These findings revealed that C/EBP alpha and HNF-3 gamma cooperatively regulate CYP3A4 expression in hepatic cells by a mechanism that probably involves chromatin remodeling.
Regulation of sequence-specific DNA binding transcription factor activitydefinition[GO:0051090]‹silver
Any process that modulates the frequency, rate or extent of the activity of a transcription factor, any factor involved in the initiation or regulation of transcription.
Protein involved in differentiation, the developmental process of a multicellular organism by which cells become specialized for particular functions. Differentiation requires selective expression of the genome; the fully differentiated state may be preceded by a stage in which the cell is already programmed for differentiation but is not yet expressing the characteristic phenotype determination. Also used for fungal conidiation proteins, and for some bacteria that present specialization of function in cell types, such as Caulobacter crescentus.
Protein involved in sperm cell development. A process whereby primordial germ cells form mature spermatozoa, which includes spermatocytogenesis (successive mitotic and meiotic divisions) and spermiogenesis (a metamorphic change).
Protein involved in the transfer of genetic information from DNA to messenger RNA (mRNA) by DNA-directed RNA polymerase. In the case of some RNA viruses, protein involved in the transfer of genetic information from RNA to messenger RNA (mRNA) by RNA-directed RNA polymerase.
Protein involved in development, the process whereby a multicellular organism develops from its early immature forms, e.g., zygote, larva, embryo, into an adult.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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