Disease relevance of USF1

• Like hypoxia, inhibitory effects of proteasome inhibitors on hCYP19 expression were mediated by increased binding of USF1/2 to the E-boxes [1].
• Transcription factors USF1 and USF2 up-regulate gene expression (i.e. , HIV-1 long terminal repeats) via interaction with an E box on their target promoters, which is also a binding site for c-Myc [2].
• In transiently transfected HeLa or hepatoma cells, USF2a and USF1 homodimers transactivated a minimal promoter with similar efficiency, whereas USF2b, which lacks an internal 67-amino acid domain, was a poor transactivator [3].
• To explore this possibility, we compared the activities of the ubiquitous USF1 and USF2 proteins in several cell lines derived from either normal breast epithelium or breast tumors [4].
• Overexpression of USF1 in U87 glioblastoma cells led to an increased activity of the promoter that was partially mediated by the atypical E-box [5].

Psychiatry related information on USF1

• Genetic association between USF 1 and USF 2 gene polymorphisms and Japanese Alzheimer's disease [6].
• A mutation that abolishes upstream stimulatory factor binding, either alone or in combination with the alpha EB1 mutation, reduces basal activity of the promoter to approximately 21% of control levels in alpha T3-1 cells and abolishes the decrease in promoter activity seen when Id is overexpressed [7].

High impact information on USF1

• USF1 encodes a transcription factor known to regulate several genes of glucose and lipid metabolism [8].
• Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1) [8].
• Expression profiles in fat biopsy samples from individuals with FCHL seemed to differ depending on their carrier status for the associated USF1 haplotype [8].
• Familial combined hyperlipidemia (FCHL, MIM-144250) is a common, multifactorial and heterogeneous dyslipidemia predisposing to premature coronary artery disease and characterized by elevated plasma triglycerides, cholesterol, or both [9].
• A major late promoter transcription factor MLTF has been detected as a discrete protein-DNA complex [10].

Chemical compound and disease context of USF1

• Upstream transcription factor 1 (USF1), the first gene associated with familial combined hyperlipidemia (FCHL), regulates numerous genes of glucose and lipid metabolism [11].
• In summary, we have demonstrated a novel mechanism for USF activation, which contributes to differential vasopressin expression in lung cancer [12].
• The adenovirus major late transcription factor USF is a member of the helix-loop-helix group of regulatory proteins and binds to DNA as a dimer [13].
• The gene encoding the transcription factor upstream stimulatory factor (USF)1 influences susceptibility to familial combined hyperlipidemia (FCHL) and triglyceride levels [14].
• Upstream stimulatory factor 1 associated with familial combined hyperlipidemia, LDL cholesterol, and triglycerides [15].

Biological context of USF1

• The USF1 and USF2 proteins contain highly divergent transcriptional activation domains but share extensive homologies in the bHLH-zip region and recognize the same CACGTG DNA motifs [16].
• USF1 and 2 bound to the E-box motif in the TME and strongly transactivated the PF4 promoter [17].
• Thus, these studies demonstrate that the novel TME binding transcription factors, USF1 and 2, transactivate rat and human PF4 promoters and may play an important role in megakaryocytic gene expression [17].
• Whereas USF1 contained only an extended activation domain, USF2 contained both an activation domain and a negative regulatory region [18].
• In the second trimester, increased O(2) tension promotes proteasomal degradation of USF1/2, resulting in syncytiotrophoblast differentiation and induction of hCYP19 expression [1].

Anatomical context of USF1

• To determine whether increased O(2) might enhance proteasomal degradation of USF1/2, human trophoblasts were cultured in 2% or 20% O(2) with or without proteasome inhibitors [1].
• In human trophoblast cells cultured in 20% O(2), increased polyubiquitylation of USF1/2 proteins was observed [1].
• Furthermore, physiologic bindings of USF1 and 2 to the TME in rat megakaryocytes were demonstrated by the chromatin immunoprecipitation (ChIP) assay [17].
• The DNA-binding activities of USF1 and USF2 were present at similar levels in all cell lines [4].
• Analysis of activation of the cloned APC promoter by USF1 and USF2 in transient transfection assays in HCT-116 cells demonstrated that mutation of the E-box B site completely abolished the basal promoter activity [19].

Associations of USF1 with chemical compounds

• Additionally, USF2b was an efficient as USF1 and USF2a homodimers in transactivating the liver-specific pyruvate kinase gene promoter [3].
• We found that the E-box bound two factors, the USF1/USF2 protein and an unidentified ubiquitous protein which was named factor U [20].
• Incorporation of a mutant E box into the wild-type CD promoter/chloramphenicol acetyltransferase gene abolished USF binding and reduced the levels of both basal and estrogen-stimulated transcription [21].
• Upstream stimulatory factor activates the vasopressin promoter via multiple motifs, including a non-canonical E-box [12].
• These results suggest that one pathway by which apigenin inhibits COX-2 expression is through modulation of USF transcriptional activity [22].

Physical interactions of USF1

• In gel mobility shift and chromatin immunoprecipitation (CHIP) assays, we found that the USF suppression is through direct binding at the E-box site of hTERT promoter and rendering the effect actively [23].
• Chromatin immunoprecipitation (ChIP) demonstrated that USF proteins bind the PIGR promoter in vivo, which is enriched in acetylated histones [24].
• Using an oligonucleotide precipitation assay for USF from nuclear extracts, we demonstrate that phosphorylated USF1 fails to bind to the APOA5 promoter [25].
• In vitro translated USF1/BD possessed DNA binding activity as a homodimer and a heterodimer with USF1 (wt) [26].
• Adenovirus-mediated overexpression of a dominant negative form of USF2 decreased binding of endogenous USF to the E-box element by approximately 90% [27].

Regulatory relationships of USF1

• In a transient expression assay, the truncated USF had a dominant-negative effect on both exogenous full-length USF and endogenous positive regulators for activating TERT expression [28].
• Thus, early in gestation when the placenta is relatively hypoxic, increased USF1/2 may block trophoblast differentiation and hCYP19 gene expression [1].
• Activation of the rat follicle-stimulating hormone receptor promoter by steroidogenic factor 1 is blocked by protein kinase a and requires upstream stimulatory factor binding to a proximal E box element [29].
• TFII-I regulates induction of chromosomally integrated human immunodeficiency virus type 1 long terminal repeat in cooperation with USF [30].
• Overexpression of upstream stimulating factor-1 (USF1) suppresses the activity of the human FSH-R promoter/enhancer via Inr and E-box elements [31].

Other interactions of USF1

• The 5'-flanking sequences of the human IGF2R gene contain multiple, highly conserved E boxes almost identical to the consensus USF DNA-binding sequence [32].
• Regulation of telomerase reverse transcriptase gene activity by upstream stimulatory factor [33].
• Down-regulation of the polymeric immunoglobulin receptor in non-small cell lung carcinoma: correlation with dysregulated expression of the transcription factors USF and AP2 [34].
• Cotransfections in Drosophila Mel-2 cells confirmed promoter activation by USF1 and GATA1 [35].
• It is possible that USF lose the inhibitory effect on hTERT expression leading to telomerase reactivation and oral carcinogenesis [23].

Analytical, diagnostic and therapeutic context of USF1

• Expressions of USF1 and 2 were detected by reverse-transcriptase-polymerase chain reaction (RT-PCR) in the human megakaryocytes derived from CD34+ cells [17].
• In vitro gel shift analysis revealed distinct and TPA-dependent binding of USF1 and USF2 to the repressor element that required nucleotides within the E-box [36].
• A physical association between USF1 and GATA1 was demonstrated by their co-immunoprecipitation [35].
• By real time PCR analysis of transfected HepG2 cells, USF1 and GATA1 increased endogenous hRFC-A1/A2 transcripts [35].
• Immunoprecipitation (IP) and immunoblotting (IB) analysis reveal that the suppression of hTERT by USF was not through the interaction of USF with c-myc or mad, nor disturbed the cellular protein levels of those [23].

References