Alternative titles; symbols
HGNC Approved Gene Symbol: USF2
Cytogenetic location: 19q13.12 Genomic coordinates (GRCh38): 19:35,268,962-35,279,821 (from NCBI)
The ubiquitously expressed upstream stimulatory factor (USF) is involved in transcription of a wide variety of cellular genes and consists of 2 related polypeptides, USF1 (191523), of 43 kD, and USF2, of 44 kD (Viollet et al., 1996).
Sirito et al. (1994) cloned mouse Usf2. The 3-prime UTR of mouse Usf2 shows strong conservation with almost the entire 3-prime UTR of human USF2, and the deduced mouse and human proteins share almost complete identity. In addition to the full-length 44-kD protein, in vitro translation of mouse Usf2 resulted in a 17.5-kD protein that was translated from an internal methionine. Sirito et al. (1994) stated that human USF2 also has an alternative internal translation start site.
Viollet et al. (1996) cloned 2 USF2 splice variants from a liver cDNA library. The USF2a variant encodes a 44-kD protein, and the USF2b variant encodes a 38-kD protein. The 346-amino acid USF2a protein contains an N-terminal acidic region, followed by a proline-rich region, a basic helix-loop-helix, and a leucine zipper. Compared with USF2a, the 279-amino acid USF2b protein lacks an internal 67-amino acid stretch that includes the proline-rich region.
By Northern blot analysis of a variety of human tissues, Groenen et al. (1996) detected ubiquitous expression of the USF2 gene. In most tissues, transcripts of 2.4 and 1.8 kb were detected. An additional transcript of about 1.0 kb was detected in heart and skeletal muscle.
Sirito et al. (1994) found that mouse Usf1 and Usf2 had similar DNA-binding properties.
Viollet et al. (1996) found that USF1/USF2a heterodimers represented more than 66% of the USF binding activity in vivo, whereas USF1 and USF2a homodimers represented less that 10%. USF1/USF2b heterodimers accounted for almost 15% of the USF species in some cell lines. The preferential heterodimerization of USF subunits was reproduced ex vivo, but in vitro cotranslated subunits or recombinant USF proteins dimerized randomly. In transiently transfected HeLa or hepatoma cells, USF2a and USF1 homodimers transactivated a minimal promoter with similar efficiency, whereas USF2b was a poor transactivator of the minimal promoter. USF1, USF2a, and USF2b homodimers were equally efficient in transactivating the liver-specific pyruvate kinase gene (609712) promoter.
By cotransfection in HepG2 cells, Ribeiro et al. (1999) found that mammalian USF2a transactivated the minimal promoter AB of APOA2 (107670). All 3 E-box motifs present in elements AB, K, and L were necessary for maximum transactivation by USF2a. A dominant-negative form of USF2a inhibited the activity of the APOA2 promoter. The USF1/USF2a heterodimer, which is naturally expressed in the liver, was as efficient as the USF2a homodimer in transactivation of APOA2 promoter/enhancer constructs. By cotransfection in COS-1 cells, Ribeiro et al. (1999) showed that mammalian HNF4 (600281) synergized with USF2a in the transactivation of the APOA2 promoter. HNF4 and USF2a bound to the enhancer cooperatively, which Ribeiro et al. (1999) suggested may account for the transcriptional synergism observed.
Resting human lymphocytes do not have telomerase activity, but activation by a variety of stimuli induces TERT (187270) expression and telomerase activity. Yago et al. (2002) found that activated human T and B lymphocytes expressed USF1 and the full-length isoform of USF2, and that dimers of these proteins bound E boxes in the TERT promoter and activated TERT expression. In contrast, resting human T and B lymphocytes expressed both the N-terminally truncated isoform of USF2 and full-length USF2, and the truncated isoform had a dominant-negative effect on TERT expression induced by full-length USF2.
Groenen et al. (1996) determined that the USF2 gene contains 10 exons distributed over a DNA region of about 11 kb. The putative promoter region is GC rich and lacks TATA and CCAAT boxes, suggesting that expression of the USF2 gene may be controlled by a typical housekeeping gene promoter.
Henrion et al. (1995) showed that the Usf2 gene in the mouse consists of at least 10 exons spanning a minimum of 10 kb of genomic DNA.
By isotopic in situ hybridization, Henrion et al. (1995) mapped the Usf2 gene to mouse chromosome 7. In the mouse, using interspecific backcross analysis, Steingrimsson et al. (1995) demonstrated that the Usf2 gene is located on chromosome 7 in a region that shows homology of synteny to human 19q13. They suggested, therefore, that 19q is the site of the human gene.
By genomic sequence analysis, Groenen et al. (1996) mapped the USF2 gene to chromosome 19q13.1.
Fryns et al. (1993) and Moerman et al. (1994) described a reciprocal translocation involving 6p and 19q in a patient with bilateral multicystic renal dysplasia (MCRD) and bilateral pelviureteric junction obstruction (PUJO) resulting in massive hydronephrosis (143400). The karyotype of the patient with the de novo chromosomal translocation was 46,XX,t(6;19)(p21;q13.1). To determine the relationship between the translocation and hereditary hydronephrosis, Groenen et al. (1996) carried out molecular characterization of a chromosome 19 cosmid clone previously identified as spanning the translocation in this unique index case. DNA sequencing of a fragment that straddled the translocation indicated the presence of DNA sequences with a high degree of similarity to the USF2 gene. The chromosome 19 breakpoint in the MCRD patient appeared to have occurred in intron 7 of the USF2 gene. Northern blot and 3-prime RACE analysis of mRNA isolated from lung fibroblasts of the MCRD patient failed to detect a fusion transcript involving USF2 sequences, suggesting to Groenen et al. (1996) that gene disruption rather than the generation of a fusion gene may be the underlying mechanism. Groenen et al. (1998) determined that the chromosome 6 breakpoint in this patient resides in intron 9 of the CDC5L gene (602868).
By analyzing the glucose responsiveness of Usf knockout mice, Vallet et al. (1998) determined that normal responsiveness required either Usf1/Usf2 heterodimers or Usf2 homodimers, even in mice with total Usf binding activity reduced by half. Usf1 homodimers gave rise to delayed glucose responsiveness.
Casado et al. (1999) stated that the E box within the FASN (600212) promoter is regulated by USF1, USF2, and SREBP1 (184756). They analyzed the glucose responsiveness of hepatic Fasn gene expression in Usf1 and Usf2 knockout mice and found that in both types of mutant mice, induction of the Fasn gene by refeeding a carbohydrate-rich diet was severely delayed. In contrast, expression of Srebp1 was almost normal, and insulin response was unchanged. Casado et al. (1999) concluded that the USF transactivators, and especially USF1/USF2 heterodimers, are essential to sustain the dietary induction of the FASN gene in liver.
Casado, M., Vallet, V. S., Kahn, A., Vaulont, S. Essential role in vivo of upstream stimulatory factors for a normal dietary response of the fatty acid synthase gene in the liver. J. Biol. Chem. 274: 2009-2013, 1999. [PubMed: 9890958] [Full Text: https://doi.org/10.1074/jbc.274.4.2009]
Fryns, J. P., Kleczkowska, A., Moerman, P., Vandenberghe, K. Hereditary hydronephrosis and the short arm of chromosome 6. (Letter) Hum. Genet. 91: 514-515, 1993. [PubMed: 8357406] [Full Text: https://doi.org/10.1007/BF00217787]
Groenen, P. M. A., Garcia, E., Debeer, P., Devriendt, K., Fryns, J. P., Van de Ven, W. J. M. Structure, sequence, and chromosome 19 localization of human USF2 and its rearrangement in a patient with multicystic renal dysplasia. Genomics 38: 141-148, 1996. [PubMed: 8954795] [Full Text: https://doi.org/10.1006/geno.1996.0609]
Groenen, P. M. A., Vanderlinden, G., Devriendt, K., Fryns, J.-P, Van de Ven, W. J. M. Rearrangement of the human CDC5L gene by a t(6;19)(p21;q13.1) in a patient with multicystic renal dysplasia. Genomics 49: 218-229, 1998. [PubMed: 9598309] [Full Text: https://doi.org/10.1006/geno.1998.5254]
Henrion, A. A., Martinez, A., Mattei, M.-G., Kahn, A., Raymondjean, M. Structure, sequence, and chromosomal location of the gene for USF2 transcription factors in mouse. Genomics 25: 36-43, 1995. [PubMed: 7774954] [Full Text: https://doi.org/10.1016/0888-7543(95)80107-w]
Moerman, P., Fryns, J.-P., Sastrowijoto, S. H., Vandenberghe, K., Lauweryns, J. M. Hereditary renal adysplasia: new observations and hypotheses. Pediat. Path. 14: 405-410, 1994. [PubMed: 8065999] [Full Text: https://doi.org/10.3109/15513819409024271]
Ribeiro, A., Pastier, D., Kardassis, D., Chambaz, J., Cardot, P. Cooperative binding of upstream stimulatory factor and hepatic nuclear factor 4 drives the transcription of the human apolipoprotein A-II gene. J. Biol. Chem. 274: 1216-1225, 1999. [PubMed: 9880489] [Full Text: https://doi.org/10.1074/jbc.274.3.1216]
Sirito, M., Lin, Q., Maity, T., Sawadogo, M. Ubiquitous expression of the 43- and 44-kDa forms of transcription factor USF in mammalian cells. Nucleic Acids Res. 22: 427-433, 1994. [PubMed: 8127680] [Full Text: https://doi.org/10.1093/nar/22.3.427]
Steingrimsson, E., Sawadogo, M., Gilbert, D. J., Zervos, A. S., Brent, R., Blanar, M. A., Fisher, D. E., Copeland, N. G., Jenkins, N. A. Murine chromosomal location of five bHLH-Zip transcription factor genes. Genomics 28: 179-183, 1995. [PubMed: 8530024] [Full Text: https://doi.org/10.1006/geno.1995.1129]
Vallet, V. S., Casado, M., Henrion, A. A., Bucchini, D., Raymondjean, M., Kahn, A., Vaulont, S. Differential roles of upstream stimulatory factors 1 and 2 in the transcriptional response of liver genes to glucose J. Biol. Chem. 273: 20175-20179, 1998. [PubMed: 9685363] [Full Text: https://doi.org/10.1074/jbc.273.32.20175]
Viollet, B., Lefrancois-Martinez, A. M., Henrion, A., Kahn, A., Raymondjean, M., Martinez, A. Immunochemical characterization and transacting properties of upstream stimulatory factor isoforms. J. Biol. Chem. 271: 1405-1415, 1996. [PubMed: 8576131] [Full Text: https://doi.org/10.1074/jbc.271.3.1405]
Yago, M., Ohki, R., Hatakeyama, S., Fujita, T., Ishikawa, F. Variant forms of upstream stimulatory factors (USFs) control the promoter activity of hTERT, the human gene encoding the catalytic subunit of telomerase. FEBS Lett. 520: 40-46, 2002. [PubMed: 12044867] [Full Text: https://doi.org/10.1016/s0014-5793(02)02757-6]