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| Functional domains of the USF1 protein. The A1 domain is important for E-box dependent transactivation, the USR (USF-specific region) and A2 domains are important for E-box and initiator element (Inr)-dependent transactivation (Roy et al., 1997). Post-translational modifications that affect USF1 function are indicated. The protein product of the splice variant lacks the first 59 amino acids, dimerizes with full-length USF1 protein, which results in its inactivation (Saito et al., 2003). |
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Description | USF1 belongs to the bHLH-Zip class of transcription factors. The bHLH-ZIP domains are important for DNA binding and dimerization. USF homo- and heterodimers activate transcription of target genes through binding either at distal E-box elements or at pyrimidine-rich Inr elements in the core promoter (Roy et al., 1997). Whole genome ChIP-chip analysis in human hepatoma HepG2 cells showed that USF1 and USF2 bind predominantly to CACGTGAC elements (Rada-Iglesias et al., 2008). In addition, USF2 but not USF1 binds to pyrimidine rich elements, suggesting that transactivation through Inr elements is mainly through USF2. Transactivation activity critically depends on post-translational modification of USF1. DNA binding to the E-box element is increased by phosphorylation of USF1 by the cdk1, p38 stress-activated kinase, protein kinase A and protein kinase C pathway (Corre and Galibert, 2005), whereas phosphorylation through the PI3Kinase pathway leads to loss of DNA binding activity to the ApoAV promoter (Nowak et al., 2005). Cellular stress stimuli such as DNA damage, oxidative stress and heavy metal exposure, induce p38-mediated phosphorylation at T153 and increased USF1 transactivation activity. Upon increased and/or prolonged stress exposure, USF1 phosphorylated at T153 becomes acetylated at K199 with concomitant loss of transactivation activity (Corre et al., 2009). In fasting-refeeding cycles, insulin increases the transactivation activity of USF1 via DNA-PK mediated phosphorylation of residue S262 and subsequent acetylation at K237 (Wong et al., 2009). |
Expression | The USF1 gene is ubiquitously expressed (Sirito et al., 1994). |
Localisation | The USF1 protein is located in the nucleus. |
Function | USF1 has been shown to play an important role in transcriptional regulation of a huge number of seemingly unrelated genes (Corre and Galibert, 2005; Rada-Iglesias et al., 2008), consistent with the abundant distribution of E-box like elements in the genome. Whole-genome ChIP analysis in HepG2 cells identified 2518 USF1 binding sites in chromatin context, of which 41 % were located within 1 kb of a transcription start site (Rade-Iglesias et al., 2008). USF1 binding signals strongly correlate with target gene expression levels, suggesting that USF1 plays an important role in transcription activation. USF1 physically interacts with histone modifying enzymes, transcription preinitiation complex factors, coactivator and corepressor proteins (Corre and Galibert, 2005; Huang et al., 2007; Corre et al., 2009; Wong et al., 2009). In addition, USF1 interacts with other transcription factors to achieve cooperative transcriptional activation of individual genes (Corre and Galibert, 2005). USF1 also plays a crucial role in chromatin barrier insulator function, in which euchromatin regions are protected from heterochromatin-induced gene silencing (Huang et al., 2007). USFs recruit histone modifying enzymes to the insulator element, which modify the adjacent nucleosomes thereby maintaining chromatin in an open state and preventing heterochromatin spread. Similarly, USFs main function at enhancer elements may be to render the adjacent region accessible for binding of other, bona fide transcription factors, by the recruitment of histone modifying enzymes (Huang et al., 2007). Tumor suppression: Several lines of evidence support the hypothesis that USF1 may act as a tumor suppressor. First, USF1 is involved in the transcriptional activation of several tumor suppressor genes (e.g. p53, APC, BRCA2, PTEN, SSeCKS) (Corre and Galibert, 2005; Pezzolesi et al., 2007; Bu and Gelman, 2007), and represses expression of human telomerase reverse transcriptase TERT (McMurray and McCance, 2003; Chang et al., 2005). Second, USF1 is involved in cell cycle control (Cogswell et al., 1995) and overexpression of USF1 slows G2/M transition in thyrocytes and thyroid carcinoma cells (Jung et al., 2007). Third, USF1 overexpression leads to a strong reduction in cell proliferation in Ha-Ras/c-Myc transformed fibroblasts (Luo and Sawadogo, 1996). Fourth, USF1 transactivation activity is completely lost in three out of six transformed breast cell lines (Ismail et al., 1999). Fifth, USF1 antagonizes some activities of the oncoprotein c-Myc, possibly by competing for the same DNA binding sites (Luo and Sawadogo, 1996; McMurray and McCance, 2003). Definitive proof that USF1 is a tumor suppressor protein, e.g. showing that USF1 knockdown increases cell proliferation and tumor formation, however, is still missing. This proof may be hard to gain, as USF2 may compensate for USF1 loss, and USF2 appears to have a broader antiproliferative function than USF1 (Luo and Sadawogo, 1996; Sirito et al., 1998; Vallet et al., 1998). |
Homology | The USF1 gene is widely conserved with orthologs identified in Ciona intestinalis and Drosophila melanogaster. |
v-Src-mediated down-regulation of SSeCKS metastasis suppressor gene promoter by the recruitment of HDAC1 into a USF1-Sp1-Sp3 complex. |
Bu Y, Gelman IH. |
J Biol Chem. 2007 Sep 14;282(37):26725-39. Epub 2007 Jul 10. |
PMID 17626016 |
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Upstream stimulatory factor (USF) as a transcriptional suppressor of human telomerase reverse transcriptase (hTERT) in oral cancer cells. |
Chang JT, Yang HT, Wang TC, Cheng AJ. |
Mol Carcinog. 2005 Nov;44(3):183-92. |
PMID 16010690 |
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Upstream stimulatory factor regulates expression of the cell cycle-dependent cyclin B1 gene promoter. |
Cogswell JP, Godlevski MM, Bonham M, Bisi J, Babiss L. |
Mol Cell Biol. 1995 May;15(5):2782-90. |
PMID 7739559 |
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Upstream stimulating factors: highly versatile stress-responsive transcription factors. |
Corre S, Galibert MD. |
Pigment Cell Res. 2005 Oct;18(5):337-48. |
PMID 16162174 |
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Target gene specificity of USF-1 is directed via p38-mediated phosphorylation-dependent acetylation. |
Corre S, Primot A, Baron Y, Le Seyec J, Goding C, Galibert MD. |
J Biol Chem. 2009 Jul 10;284(28):18851-62. Epub 2009 Apr 23. |
PMID 19389701 |
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USF1 recruits histone modification complexes and is critical for maintenance of a chromatin barrier. |
Huang S, Li X, Yusufzai TM, Qiu Y, Felsenfeld G. |
Mol Cell Biol. 2007 Nov;27(22):7991-8002. Epub 2007 Sep 10. |
PMID 17846119 |
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Loss of USF transcriptional activity in breast cancer cell lines. |
Ismail PM, Lu T, Sawadogo M. |
Oncogene. 1999 Sep 30;18(40):5582-91. |
PMID 10523835 |
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USF inhibits cell proliferation through delay in G2/M phase in FRTL-5 cells. |
Jung HS, Kim KS, Chung YJ, Chung HK, Min YK, Lee MS, Lee MK, Kim KW, Chung JH. |
Endocr J. 2007 Apr;54(2):275-85. Epub 2007 Mar 20. |
PMID 17379962 |
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Upstream transcription factor 1 gene polymorphisms are associated with high antilipolytic insulin sensitivity and show gene-gene interactions. |
Kantartzis K, Fritsche A, Machicao F, Stumvoll M, Machann J, Schick F, Haring HU, Stefan N. |
J Mol Med. 2007 Jan;85(1):55-61. Epub 2006 Sep 26. |
PMID 17016691 |
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Antiproliferative properties of the USF family of helix-loop-helix transcription factors. |
Luo X, Sawadogo M. |
Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):1308-13. |
PMID 8577760 |
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Human papillomavirus type 16 E6 activates TERT gene transcription through induction of c-Myc and release of USF-mediated repression. |
McMurray HR, McCance DJ. |
J Virol. 2003 Sep;77(18):9852-61. |
PMID 12941894 |
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Functional variant disrupts insulin induction of USF1: mechanism for USF1-associated dyslipidemias. |
Naukkarinen J, Nilsson E, Koistinen HA, Soderlund S, Lyssenko V, Vaag A, Poulsen P, Groop L, Taskinen MR, Peltonen L. |
Circ Cardiovasc Genet. 2009 Oct;2(5):522-9. Epub 2009 Jun 12. |
PMID 20031629 |
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Insulin-mediated down-regulation of apolipoprotein A5 gene expression through the phosphatidylinositol 3-kinase pathway: role of upstream stimulatory factor. |
Nowak M, Helleboid-Chapman A, Jakel H, Martin G, Duran-Sandoval D, Staels B, Rubin EM, Pennacchio LA, Taskinen MR, Fruchart-Najib J, Fruchart JC. |
Mol Cell Biol. 2005 Feb;25(4):1537-48. |
PMID 15684402 |
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Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1). |
Pajukanta P, Lilja HE, Sinsheimer JS, Cantor RM, Lusis AJ, Gentile M, Duan XJ, Soro-Paavonen A, Naukkarinen J, Saarela J, Laakso M, Ehnholm C, Taskinen MR, Peltonen L. |
Nat Genet. 2004 Apr;36(4):371-6. Epub 2004 Feb 29. |
PMID 14991056 |
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Comparative genomic and functional analyses reveal a novel cis-acting PTEN regulatory element as a highly conserved functional E-box motif deleted in Cowden syndrome. |
Pezzolesi MG, Zbuk KM, Waite KA, Eng C. |
Hum Mol Genet. 2007 May 1;16(9):1058-71. Epub 2007 Mar 6. |
PMID 17341483 |
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Whole-genome maps of USF1 and USF2 binding and histone H3 acetylation reveal new aspects of promoter structure and candidate genes for common human disorders. |
Rada-Iglesias A, Ameur A, Kapranov P, Enroth S, Komorowski J, Gingeras TR, Wadelius C. |
Genome Res. 2008 Mar;18(3):380-92. Epub 2008 Jan 29. |
PMID 18230803 |
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Cloning of an inr- and E-box-binding protein, TFII-I, that interacts physically and functionally with USF1. |
Roy AL, Du H, Gregor PD, Novina CD, Martinez E, Roeder RG. |
EMBO J. 1997 Dec 1;16(23):7091-104. |
PMID 9384587 |
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Cloning and characterization of a novel splicing isoform of USF1. |
Saito T, Oishi T, Yanai K, Shimamoto Y, Fukamizu A. |
Int J Mol Med. 2003 Aug;12(2):161-7. |
PMID 12851711 |
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Overlapping roles and asymmetrical cross-regulation of the USF proteins in mice. |
Sirito M, Lin Q, Deng JM, Behringer RR, Sawadogo M. |
Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3758-63. |
PMID 9520440 |
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Differential roles of upstream stimulatory factors 1 and 2 in the transcriptional response of liver genes to glucose. |
Vallet VS, Casado M, Henrion AA, Bucchini D, Raymondjean M, Kahn A, Vaulont S. |
J Biol Chem. 1998 Aug 7;273(32):20175-9. |
PMID 9685363 |
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A role of DNA-PK for the metabolic gene regulation in response to insulin. |
Wong RH, Chang I, Hudak CS, Hyun S, Kwan HY, Sul HS. |
Cell. 2009 Mar 20;136(6):1056-72. |
PMID 19303849 |
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