upstream stimulatory factors


Summary: Ubiquitously expressed basic HELIX-LOOP-HELIX MOTIF transcription factors. They bind CANNTG sequences in the promoters of a variety of GENES involved in carbohydrate and lipid metabolism.

Top Publications

  1. Shoulders C, Naoumova R. USF1 implicated in the aetiology of familial combined hyperlipidaemia and the metabolic syndrome. Trends Mol Med. 2004;10:362-5 pubmed
    ..The use of chromatin immunoprecipitation methodologies combined with promoter microarray assays will help to define the transcriptional networks that underlie whole-body glucose and lipid homeostasis. ..
  2. Sellak H, Choi C, Browner N, Lincoln T. Upstream stimulatory factors (USF-1/USF-2) regulate human cGMP-dependent protein kinase I gene expression in vascular smooth muscle cells. J Biol Chem. 2005;280:18425-33 pubmed
    ..591 bp from the transcriptional start site revealed the existence of two E-like boxes known to bind upstream stimulatory factors. Electrophoretic mobility shift assays and functional studies using luciferase reporter gene assays ..
  3. Hoffstedt J, Ryden M, Wahrenberg H, van Harmelen V, Arner P. Upstream transcription factor-1 gene polymorphism is associated with increased adipocyte lipolysis. J Clin Endocrinol Metab. 2005;90:5356-60 pubmed
    ..02). Polymorphism in the usf1 gene is associated with increased lipolytic effect of catecholamines in fat cells, which is localized at the postadrenoceptor level, possibly, at least, involving protein kinase A. ..
  4. Chen W, West A, Tao X, Corfas G, Szentirmay M, Sawadogo M, et al. Upstream stimulatory factors are mediators of Ca2+-responsive transcription in neurons. J Neurosci. 2003;23:2572-81 pubmed
    ..the identification of a Ca(2+)-responsive E-box element, CaRE2, within BDNF promoter III that binds upstream stimulatory factors 1 and 2 (USF1/2) and show that USFs are required for the activation of CaRE2-dependent transcription ..
  5. Rada Iglesias A, Wallerman O, Koch C, Ameur A, Enroth S, Clelland G, et al. Binding sites for metabolic disease related transcription factors inferred at base pair resolution by chromatin immunoprecipitation and genomic microarrays. Hum Mol Genet. 2005;14:3435-47 pubmed
    ..Our data suggests that a similar approach could be used for the in vivo characterization of all predicted/uncharacterized TF and that the analysis could be scaled to the whole genome. ..
  6. Vallet V, Casado M, Henrion A, Bucchini D, Raymondjean M, Kahn A, et al. Differential roles of upstream stimulatory factors 1 and 2 in the transcriptional response of liver genes to glucose. J Biol Chem. 1998;273:20175-9 pubmed
    ..Furthermore, they support the view that USF2 is the functional transactivator of the glucose-responsive complex. ..
  7. Kim J, Monila H, Pandey A, Lane M. Upstream stimulatory factors regulate the C/EBP alpha gene during differentiation of 3T3-L1 preadipocytes. Biochem Biophys Res Commun. 2007;354:517-21 pubmed
    ..The expression of AP-4 is reciprocally regulated with USF-1 during adipocyte differentiation. These findings suggest that USF-1 and 2 play roles in C/EBPalpha expression, whereas the AP-4 represses it. ..
  8. Pawlus M, Wang L, Ware K, Hu C. Upstream stimulatory factor 2 and hypoxia-inducible factor 2? (HIF2?) cooperatively activate HIF2 target genes during hypoxia. Mol Cell Biol. 2012;32:4595-610 pubmed publisher
  9. Weigert C, Brodbeck K, Sawadogo M, Häring H, Schleicher E. Upstream stimulatory factor (USF) proteins induce human TGF-beta1 gene activation via the glucose-response element-1013/-1002 in mesangial cells: up-regulation of USF activity by the hexosamine biosynthetic pathway. J Biol Chem. 2004;279:15908-15 pubmed
    ..We found that high glucose concentrations enhanced the nuclear amount of upstream stimulatory factors (USF) and their binding to this sequence...

More Information


  1. Huertas Vazquez A, Aguilar Salinas C, Lusis A, Cantor R, Canizales Quinteros S, Lee J, et al. Familial combined hyperlipidemia in Mexicans: association with upstream transcription factor 1 and linkage on chromosome 16q24.1. Arterioscler Thromb Vasc Biol. 2005;25:1985-91 pubmed
    ..1 region to an FCHL-component trait in Mexicans. ..
  2. Bengtsson S, Madeyski Bengtson K, Nilsson J, Bjursell G. Transcriptional regulation of the human carboxyl ester lipase gene in THP-1 monocytes: an E-box required for activation binds upstream stimulatory factors 1 and 2. Biochem J. 2002;365:481-8 pubmed
    ..Electrophoretic mobility-shift assay analyses reveal that the E-box binds the upstream stimulatory factors 1 and 2, and the binding of an upstream stimulatory factor-containing complex in THP-1 cells also ..
  3. Imagawa S, Fujii S, Dong J, Furumoto T, Kaneko T, Zaman T, et al. Hepatocyte growth factor regulates E box-dependent plasminogen activator inhibitor type 1 gene expression in HepG2 liver cells. Arterioscler Thromb Vasc Biol. 2006;26:2407-13 pubmed
    ..Electrophoretic mobility shift assays demonstrated that this E box binds upstream stimulatory factors (USFs). HGF phosphorylated USFs through MAPK and tyrosine kinase pathways...
  4. Park S, Liu X, Davis D, Sigmund C. Gene trapping uncovers sex-specific mechanisms for upstream stimulatory factors 1 and 2 in angiotensinogen expression. Hypertension. 2012;59:1212-9 pubmed publisher
    ..In conclusion, both USF1 and USF2 are essential for AGT transcriptional regulation, and distinct sex-specific and tissue-specific mechanisms are involved in the activities of these transcription factors in vivo. ..
  5. Mrad M, Mouawad C, Al Hariri M, Eid A, Alam J, Habib A. Statins modulate transcriptional activity of heme-oxygenase-1 promoter in NIH 3T3 Cells. J Cell Biochem. 2012;113:3466-75 pubmed publisher
    ..Moreover, overexpression of mutated C/EBP ? and USF factor or the siRNA for both factors supported a role of these transcription factors in statin-dependent induction of HO-1, with a clearer effect for C/EBP. ..
  6. Qyang Y, Luo X, Lu T, Ismail P, Krylov D, Vinson C, et al. Cell-type-dependent activity of the ubiquitous transcription factor USF in cellular proliferation and transcriptional activation. Mol Cell Biol. 1999;19:1508-17 pubmed
    ..The activity of USF is therefore context dependent, and evidence for USF DNA-binding activity in particular cells is insufficient to indicate USF function in transcriptional activation and growth control. ..
  7. Casado M, Vallet V, 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. 1999;274:2009-13 pubmed
    ..b>Upstream stimulatory factors (USF1 and USF2) and sterol response element binding protein 1 (SREBP1) were shown to be able to ..
  8. Viswanathan P, Wood M, Walker W. Follicle-stimulating hormone (FSH) transiently blocks FSH receptor transcription by increasing inhibitor of deoxyribonucleic acid binding/differentiation-2 and decreasing upstream stimulatory factor expression in rat Sertoli cells. Endocrinology. 2009;150:3783-91 pubmed publisher
    ..This FSH-regulated mechanism may explain the cyclical changes in Fshr expression that occurs in Sertoli cells in vivo. ..
  9. Sadowski I, Mitchell D. TFII-I and USF (RBF-2) regulate Ras/MAPK-responsive HIV-1 transcription in T cells. Eur J Cancer. 2005;41:2528-36 pubmed
  10. Olave N, Grenett M, Cadeiras M, Grenett H, Higgins P. Upstream stimulatory factor-2 mediates quercetin-induced suppression of PAI-1 gene expression in human endothelial cells. J Cell Biochem. 2010;111:720-6 pubmed publisher
    ..Quer-induced decreases in PAI-1 expression and reduced cell proliferation may contribute, at least in part, to the cardioprotective benefit associated with daily intake of polyphenols. ..
  11. Sanchez A, Zhao J, You Y, Declèves A, Diamond Stanic M, Sharma K. Role of the USF1 transcription factor in diabetic kidney disease. Am J Physiol Renal Physiol. 2011;301:F271-9 pubmed publisher
    ..AMPK activity may play a key role in high glucose-induced regulation of USF1. ..
  12. Carabana J, Ortigoza E, Krangel M. Regulation of the murine Ddelta2 promoter by upstream stimulatory factor 1, Runx1, and c-Myb. J Immunol. 2005;174:4144-52 pubmed
    ..We speculate that the Ddelta2 promoter may play a role as a weak, enhancer-independent regulator in vivo, and might contribute to residual Tcrd rearrangement in Edelta(-/-) mice. ..
  13. Putt W, Palmen J, Nicaud V, Tregouet D, Tahri Daizadeh N, Flavell D, et al. Variation in USF1 shows haplotype effects, gene : gene and gene : environment associations with glucose and lipid parameters in the European Atherosclerosis Research Study II. Hum Mol Genet. 2004;13:1587-97 pubmed
    ..0002) on AUC TG and APOC3 -482C>T on plasma apoE levels (P=0.0012). Thus, in these healthy young men, variation in USF1 was the influencing feature of both glucose and lipid homeostasis showing case-control heterogeneity. ..
  14. Gregor P, Sawadogo M, Roeder R. 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. Genes Dev. 1990;4:1730-40 pubmed
    ..The structure of different cDNA clones indicates that USF RNA is differentially spliced, and alternative exon usage may regulate the levels of functional USF protein. ..
  15. van Deursen D, Van Leeuwen M, Vaulont S, Jansen H, Verhoeven A. Upstream Stimulatory Factors 1 and 2 activate the human hepatic lipase promoter via E-box dependent and independent mechanisms. Biochim Biophys Acta. 2009;1791:229-37 pubmed publisher
    ..We conclude that in HepG2 cells USF1 and USF2 regulate transcriptional activity of the HL gene through their binding to the E-box at -307/-312 and the TATA-Inr region. ..
  16. Terragni J, Nayak G, Banerjee S, Medrano J, Graham J, Brennan J, et al. The E-box binding factors Max/Mnt, MITF, and USF1 act coordinately with FoxO to regulate expression of proapoptotic and cell cycle control genes by phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3 signaling. J Biol Chem. 2011;286:36215-27 pubmed publisher
    ..These results define a novel E-box-regulated network that functions coordinately with FoxO to regulate transcription of apoptotic and cell cycle regulatory genes downstream of PI 3-kinase/Akt/GSK3 signaling. ..
  17. Coon H, Xin Y, Hopkins P, Cawthon R, Hasstedt S, Hunt S. Upstream stimulatory factor 1 associated with familial combined hyperlipidemia, LDL cholesterol, and triglycerides. Hum Genet. 2005;117:444-51 pubmed
    ..This study replicates the involvement of USF1 in FCHL and related lipid traits in a family sample not ascertained for FCHL. ..
  18. West A, Huang S, Gaszner M, Litt M, Felsenfeld G. Recruitment of histone modifications by USF proteins at a vertebrate barrier element. Mol Cell. 2004;16:453-63 pubmed
    ..We propose that barrier activity requires the constitutive recruitment of H3K4 methylation and histone acetylation at multiple residues to counteract the propagation of condensed chromatin structures. ..
  19. Kim S, Choi S, Chao W, Volsky D. Transcriptional regulation of human excitatory amino acid transporter 1 (EAAT1): cloning of the EAAT1 promoter and characterization of its basal and inducible activity in human astrocytes. J Neurochem. 2003;87:1485-98 pubmed
    ..Conversely, tumor necrosis factor-alpha reduced both EAAT promoter activity and cellular EAAT1 mRNA expression. These results enable studies of transcriptional regulation of EAAT1 gene at the promoter level. ..
  20. Jiang B, Mendelson C. USF1 and USF2 mediate inhibition of human trophoblast differentiation and CYP19 gene expression by Mash-2 and hypoxia. Mol Cell Biol. 2003;23:6117-28 pubmed
    ..On the other hand, the basic helix-loop-helix leucine zipper transcription factors upstream stimulatory factors 1 and 2 (USF1 and USF2) did bind to E2 and E3 but not E1...
  21. Zhu J, Giannola D, Zhang Y, Rivera A, Emerson S. NF-Y cooperates with USF1/2 to induce the hematopoietic expression of HOXB4. Blood. 2003;102:2420-7 pubmed
    ..These results suggest that NF-Y is a developmentally regulated inducer of the HOXB4 gene in hematopoietic cells. ..
  22. Coulson J, Edgson J, Marshall Jones Z, Mulgrew R, Quinn J, Woll P. Upstream stimulatory factor activates the vasopressin promoter via multiple motifs, including a non-canonical E-box. Biochem J. 2003;369:549-61 pubmed
    ..In summary, we have demonstrated a novel mechanism for USF activation, which contributes to differential vasopressin expression in lung cancer. ..
  23. Sirito M, Lin Q, Deng J, Behringer R, Sawadogo M. Overlapping roles and asymmetrical cross-regulation of the USF proteins in mice. Proc Natl Acad Sci U S A. 1998;95:3758-63 pubmed
  24. Liang S, Moghimi B, Crusselle Davis V, Lin I, Rosenberg M, Li X, et al. Defective erythropoiesis in transgenic mice expressing dominant-negative upstream stimulatory factor. Mol Cell Biol. 2009;29:5900-10 pubmed publisher
  25. Sirito M, Walker S, Lin Q, Kozlowski M, Klein W, Sawadogo M. Members of the USF family of helix-loop-helix proteins bind DNA as homo- as well as heterodimers. Gene Expr. 1992;2:231-40 pubmed
    ..This indicates that the conserved LR in human USF is not required for dimer formation, and influences only indirectly DNA-binding. ..
  26. Yasumoto K, Yokoyama K, Shibata K, Tomita Y, Shibahara S. Microphthalmia-associated transcription factor as a regulator for melanocyte-specific transcription of the human tyrosinase gene. Mol Cell Biol. 1994;14:8058-70 pubmed
    ..These results indicate that MITF is a cell-type-specific factor that is capable of activating transcription of the tyrosinase gene. ..
  27. Utsunomiya H, Cheng Y, Lin Z, Reierstad S, Yin P, Attar E, et al. Upstream stimulatory factor-2 regulates steroidogenic factor-1 expression in endometriosis. Mol Endocrinol. 2008;22:904-14 pubmed publisher
    ..Taken together, the elevated levels of USF2 in endometriosis account for, in part, the aberrant expression of SF-1 and its target gene StAR and aromatase. ..
  28. Vallet V, Henrion A, Bucchini D, Casado M, Raymondjean M, Kahn A, et al. Glucose-dependent liver gene expression in upstream stimulatory factor 2 -/- mice. J Biol Chem. 1997;272:21944-9 pubmed
    b>Upstream stimulatory factors (USF) 1 and 2 belong to the Myc family of transcription factors characterized by a basic/helix loop helix/leucine zipper domain responsible for dimerization and DNA binding...
  29. Liu S, Shi L, Wang S. Overexpression of upstream stimulatory factor 2 accelerates diabetic kidney injury. Am J Physiol Renal Physiol. 2007;293:F1727-35 pubmed
    ..Type 1 diabetes onset further augmented the urinary albumin excretion and glomerular hypertrophy in the USF2 (Tg) mice. These findings suggest that overexpression of USF2 accelerates the development of diabetic nephropathy. ..
  30. Bu Y, Gelman I. v-Src-mediated down-regulation of SSeCKS metastasis suppressor gene promoter by the recruitment of HDAC1 into a USF1-Sp1-Sp3 complex. J Biol Chem. 2007;282:26725-39 pubmed
    ..Our data suggest that suppression of the beta promoter is facilitated by Src-induced changes in the alpha promoter chromatinization mediated by a USF1-Sp1-Sp3 complex. ..
  31. Kumari D, Gabrielian A, Wheeler D, Usdin K. The roles of Sp1, Sp3, USF1/USF2 and NRF-1 in the regulation and three-dimensional structure of the Fragile X mental retardation gene promoter. Biochem J. 2005;386:297-303 pubmed
    ..We had previously shown that in mouse brain extracts two of these sites are bound by USF1/USF2 (upstream stimulatory factors 1 and 2) heterodimers and NRF-1 (nuclear respiratory factor-1)...
  32. Komulainen K, Alanne M, Auro K, Kilpikari R, Pajukanta P, Saarela J, et al. Risk alleles of USF1 gene predict cardiovascular disease of women in two prospective studies. PLoS Genet. 2006;2:e69 pubmed
  33. Meex S, van Vliet Ostaptchouk J, van der Kallen C, Van Greevenbroek M, Schalkwijk C, Feskens E, et al. Upstream transcription factor 1 (USF1) in risk of type 2 diabetes: association study in 2000 Dutch Caucasians. Mol Genet Metab. 2008;94:352-5 pubmed publisher
    ..5%. In conclusion, the major allele of rs2073658 in the USF1 gene is associated with a modestly increased risk to develop type 2 diabetes in Dutch Caucasians, with considerable impact at the population level. ..
  34. Ma Z, Jhun B, Jung S, Oh C. Binding of upstream stimulatory factor 1 to the E-box regulates the 4G/5G polymorphism-dependent plasminogen activator inhibitor 1 expression in mast cells. J Allergy Clin Immunol. 2008;121:1006-1012.e2 pubmed publisher
    ..Overexpression of wild-type USF-1 or dominant-negative USF remedies the 4G/5G-dependent PAI-1 transcription. Binding of USF-1 to the E-4G/5G regulates the 4G/5G polymorphism-dependent PAI-1 expression in MCs. ..
  35. Gongora C, Degols G, Espert L, Hua T, Mechti N. A unique ISRE, in the TATA-less human Isg20 promoter, confers IRF-1-mediated responsiveness to both interferon type I and type II. Nucleic Acids Res. 2000;28:2333-41 pubmed
    ..These inductions are strictly dependent upon of the IFN regulatory factor 1 (IRF-1). In addition, we show that the ISRE is also implicated in the constitutive transcriptional activity of Isg20 gene. ..
  36. Tada Y, Brena R, Hackanson B, Morrison C, Otterson G, Plass C. Epigenetic modulation of tumor suppressor CCAAT/enhancer binding protein alpha activity in lung cancer. J Natl Cancer Inst. 2006;98:396-406 pubmed
    ..DNA hypermethylation of the upstream C/EBPalpha promoter region, not the core promoter region as previously reported, is critical in the regulation of C/EBPalpha expression in human lung cancer. ..
  37. Dimova E, Kietzmann T. Cell type-dependent regulation of the hypoxia-responsive plasminogen activator inhibitor-1 gene by upstream stimulatory factor-2. J Biol Chem. 2006;281:2999-3005 pubmed
  38. Gibson F, Hercberg S, Froguel P. Common polymorphisms in the USF1 gene are not associated with type 2 diabetes in French Caucasians. Diabetes. 2005;54:3040-2 pubmed
  39. Okada Y, Matsuura E, Tozuka Z, Nagai R, Watanabe A, Matsumoto K, et al. Upstream stimulatory factors stimulate transcription through E-box motifs in the PF4 gene in megakaryocytes. Blood. 2004;104:2027-34 pubmed
    ..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. ..
  40. Roy A, Meisterernst M, Pognonec P, Roeder R. Cooperative interaction of an initiator-binding transcription initiation factor and the helix-loop-helix activator USF. Nature. 1991;354:245-8 pubmed
  41. Scholtz B, Kingsley Kallesen M, Rizzino A. Transcription of the transforming growth factor-beta2 gene is dependent on an E-box located between an essential cAMP response element/activating transcription factor motif and the TATA box of the gene. J Biol Chem. 1996;271:32375-80 pubmed
    ..The importance of the E-box motif described in this study is supported by the presence of an E-box motif in the same position in the chicken TGF-beta2 gene promoter. ..
  42. Viollet B, Lefrançois Martinez A, Henrion A, Kahn A, Raymondjean M, Martinez A. Immunochemical characterization and transacting properties of upstream stimulatory factor isoforms. J Biol Chem. 1996;271:1405-15 pubmed
    ..Additionally, USF2b was an efficient as USF1 and USF2a homodimers in transactivating the liver-specific pyruvate kinase gene promoter. ..
  43. Boonsaen T, Rojvirat P, Surinya K, Wallace J, Jitrapakdee S. Transcriptional regulation of the distal promoter of the rat pyruvate carboxylase gene by hepatocyte nuclear factor 3beta/Foxa2 and upstream stimulatory factors in insulinoma cells. Biochem J. 2007;405:359-67 pubmed
    ..hepatocyte nuclear factor 3beta)/Foxa2 (forkhead/winged helix transcription factor box2) and USFs (upstream stimulatory factors), USF1 and USF2, respectively...
  44. 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. 1994;22:427-33 pubmed
  45. Xing W, Archer T. Upstream stimulatory factors mediate estrogen receptor activation of the cathepsin D promoter. Mol Endocrinol. 1998;12:1310-21 pubmed
    ..These results suggest that the ER targeting of USF-1 and USF-2 is a critical step in hormone activation of CD gene transcription in human breast cancer cells. ..
  46. Dickson M, Tian X, Liu X, Davis D, Sigmund C. Upstream stimulatory factor is required for human angiotensinogen expression and differential regulation by the A-20C polymorphism. Circ Res. 2008;103:940-7 pubmed publisher
    ..We conclude that USF1 functionally and differentially regulates AGT expression via the -20 polymorphism and that the differential expression exhibited by -20 can be accounted for by differential association with USF1. ..
  47. Hermann B, Hornbaker K, Rice D, Sawadogo M, Heckert L. In vivo regulation of follicle-stimulating hormone receptor by the transcription factors upstream stimulatory factor 1 and upstream stimulatory factor 2 is cell specific. Endocrinology. 2008;149:5297-306 pubmed publisher
  48. Amir Zilberstein L, Dikstein R. Interplay between E-box and NF-kappaB in regulation of A20 gene by DRB sensitivity-inducing factor (DSIF). J Biol Chem. 2008;283:1317-23 pubmed
    ..These findings reveal a dynamic regulation of DSIF involving either E-box or NF-kappaB depending on the physiological circumstances. ..
  49. Zhong G, Fan T, Liu L. Chlamydia inhibits interferon gamma-inducible major histocompatibility complex class II expression by degradation of upstream stimulatory factor 1. J Exp Med. 1999;189:1931-8 pubmed
    ..These results reveal a novel immune evasion strategy used by the intracellular bacterial pathogen chlamydia that improves our understanding of the molecular basis of pathogenesis. ..
  50. Ng M, Miyake K, So W, Poon E, Lam V, Li J, et al. The linkage and association of the gene encoding upstream stimulatory factor 1 with type 2 diabetes and metabolic syndrome in the Chinese population. Diabetologia. 2005;48:2018-24 pubmed
  51. Corre S, Primot A, Sviderskaya E, Bennett D, Vaulont S, Goding C, et al. UV-induced expression of key component of the tanning process, the POMC and MC1R genes, is dependent on the p-38-activated upstream stimulating factor-1 (USF-1). J Biol Chem. 2004;279:51226-33 pubmed
    ..The results define USF-1 as a critical UV-responsive activator of genes implicated in protection from solar radiation. ..
  52. van der Vleuten G, Isaacs A, Hijmans A, van Duijn C, Stalenhoef A, de Graaf J. The involvement of upstream stimulatory factor 1 in Dutch patients with familial combined hyperlipidemia. J Lipid Res. 2007;48:193-200 pubmed
    ..In conclusion, the previously identified risk haplotype of USF1 showed a suggestive association with FCH and contributed to the related lipid traits in our Dutch FCH families. ..
  53. Liu Y, Shi Z, Silveira A, Liu J, Sawadogo M, Yang H, et al. Involvement of upstream stimulatory factors 1 and 2 in RANKL-induced transcription of tartrate-resistant acid phosphatase gene during osteoclast differentiation. J Biol Chem. 2003;278:20603-11 pubmed
    ..Various assays reveal that nuclear proteins binding to the 12-bp sequence are upstream stimulatory factors (USF) 1 and 2...