e box elements


Summary: DNA locations with the consensus sequence CANNTG. ENHANCER ELEMENTS may contain multiple copies of this element. E-boxes play a regulatory role in the control of transcription. They bind with basic helix-loop-helix (bHLH) type TRANSCRIPTION FACTORS. Binding specificity is determined by the specific bHLH heterodimer or homodimer combination and by the specific nucleotides at the 3rd and 4th position of the E-box sequence.

Top Publications

  1. Perini G, Diolaiti D, Porro A, Della Valle G. In vivo transcriptional regulation of N-Myc target genes is controlled by E-box methylation. Proc Natl Acad Sci U S A. 2005;102:12117-22 pubmed
    ..This study illuminates a central role of DNA methylation in controlling N-Myc occupancy at gene promoters and modulating its transcriptional activity in cancer cells. ..
  2. Muñoz E, Brewer M, Baler R. Circadian Transcription. Thinking outside the E-Box. J Biol Chem. 2002;277:36009-17 pubmed
    ..Results of this comparison will help elucidate the manner in which discreet DNA modules associate to either augment or restrain the activation of potential circadian E-Boxes in response to competing regulatory signals. ..
  3. Akashi M, Ichise T, Mamine T, Takumi T. Molecular mechanism of cell-autonomous circadian gene expression of Period2, a crucial regulator of the mammalian circadian clock. Mol Biol Cell. 2006;17:555-65 pubmed
    ..Our results provide not only compelling evidence in support of this model but also an explanation for a general basic mechanism to produce various patterns in the phase and amplitude of cell-autonomous circadian gene expression. ..
  4. Etzioni S, Yafe A, Khateb S, Weisman Shomer P, Bengal E, Fry M. Homodimeric MyoD preferentially binds tetraplex structures of regulatory sequences of muscle-specific genes. J Biol Chem. 2005;280:26805-12 pubmed
  5. Shklover J, Etzioni S, Weisman Shomer P, Yafe A, Bengal E, Fry M. MyoD uses overlapping but distinct elements to bind E-box and tetraplex structures of regulatory sequences of muscle-specific genes. Nucleic Acids Res. 2007;35:7087-95 pubmed
    ..Only deletion of all three basic clusters abolished the binding of tetraplex DNA. Implications of the binding of E-box and tetraplex DNA by non-identical MyoD elements are considered. ..
  6. Nair S, Burley S. X-ray structures of Myc-Max and Mad-Max recognizing DNA. Molecular bases of regulation by proto-oncogenic transcription factors. Cell. 2003;112:193-205 pubmed
    ..The Myc-Max heterodimer, but not its Mad-Max counterpart, dimerizes to form a bivalent heterotetramer, which explains how Myc can upregulate expression of genes with promoters bearing widely separated E boxes. ..
  7. Yafe A, Etzioni S, Weisman Shomer P, Fry M. Formation and properties of hairpin and tetraplex structures of guanine-rich regulatory sequences of muscle-specific genes. Nucleic Acids Res. 2005;33:2887-900 pubmed
    ..These results are consistent with a role of tetrahelical structures of DNA in the regulation of muscle-specific gene expression. ..
  8. Matsumoto A, Ukai Tadenuma M, Yamada R, Houl J, Uno K, Kasukawa T, et al. A functional genomics strategy reveals clockwork orange as a transcriptional regulator in the Drosophila circadian clock. Genes Dev. 2007;21:1687-700 pubmed
  9. Cotterman R, Jin V, Krig S, Lemen J, Wey A, Farnham P, et al. N-Myc regulates a widespread euchromatic program in the human genome partially independent of its role as a classical transcription factor. Cancer Res. 2008;68:9654-62 pubmed publisher
    ..These findings support a new dual model for Myc chromatin function with important implications for the role of Myc in cancer and stem cell biology, including that of induced pluripotent stem cells. ..

More Information


  1. Espineda C, Chang J, Twiss J, Rajasekaran S, Rajasekaran A. Repression of Na,K-ATPase beta1-subunit by the transcription factor snail in carcinoma. Mol Biol Cell. 2004;15:1364-73 pubmed
    ..These results suggest that down-regulation of Na,K-ATPase beta1-subunit and E-cadherin by Snail are associated with events leading to epithelial to mesenchymal transition. ..
  2. Yoo S, Ko C, Lowrey P, Buhr E, Song E, Chang S, et al. A noncanonical E-box enhancer drives mouse Period2 circadian oscillations in vivo. Proc Natl Acad Sci U S A. 2005;102:2608-13 pubmed
    ..Last, genetic analysis with mutations in Clock and Bmal1 shows that the E2 enhancer is a target of CLOCK and BMAL1 in vivo. ..
  3. Vallone D, Gondi S, Whitmore D, Foulkes N. E-box function in a period gene repressed by light. Proc Natl Acad Sci U S A. 2004;101:4106-11 pubmed
    ..Thus, these results reveal flexibility in the phase and light responsiveness of E-box-directed rhythmic expression, depending on the promoter context. ..
  4. Slack A, Chen Z, Tonelli R, Pule M, Hunt L, Pession A, et al. The p53 regulatory gene MDM2 is a direct transcriptional target of MYCN in neuroblastoma. Proc Natl Acad Sci U S A. 2005;102:731-6 pubmed
    ..Our finding that MYCN directly modulates baseline MDM2 levels suggests a mechanism contributing to the pathogenesis of neuroblastoma and other MYC-driven malignancies through inhibition of MYC-stimulated apoptosis. ..
  5. Kondratov R, Vykhovanets O, Kondratova A, Antoch M. Antioxidant N-acetyl-L-cysteine ameliorates symptoms of premature aging associated with the deficiency of the circadian protein BMAL1. Aging (Albany NY). 2009;1:979-87 pubmed
    ..We speculate that BMAL1 controls antioxidant defense by regulating the expression of major antioxidant enzymes...
  6. Pezzolesi M, Zbuk K, Waite K, Eng C. 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. Hum Mol Genet. 2007;16:1058-71 pubmed
  7. Fürbass R, Tomek W, Vanselow J. Upstream stimulating factors 1 and 2 enhance transcription from the placenta-specific promoter 1.1 of the bovine cyp19 gene. BMC Mol Biol. 2010;11:5 pubmed publisher
    ..From these results we conclude that USF1 and USF2 are activators of the bovine placenta-specific promoter P1.1 and thus act in the opposite mode as in the case of the non-orthologous human placenta-specific promoter. ..
  8. 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. ..
  9. 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
    ..Targeting HGF signaling pathway may modulate the thrombotic risk in high-risk patients. ..
  10. Alexander N, Tran N, Rekapally H, Summers C, Glackin C, Heimark R. N-cadherin gene expression in prostate carcinoma is modulated by integrin-dependent nuclear translocation of Twist1. Cancer Res. 2006;66:3365-9 pubmed
  11. 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. ..
  12. Semov A, Marcotte R, Semova N, Ye X, Wang E. Microarray analysis of E-box binding-related gene expression in young and replicatively senescent human fibroblasts. Anal Biochem. 2002;302:38-51 pubmed
    ..Alterations in the expression of E-box-binding transcription factors and c-Myc-binding proteins demonstrate the importance of these genes in establishing the contact-inhibited quiescent or senescent phenotypes. ..
  13. Chae S, Kim J, Yun Y, Lee W, Kim J, Kim Y, et al. Identification and analysis of the promoter region of the human PLC-delta4 gene. Mol Biol Rep. 2007;34:69-77 pubmed
    ..These results will provide important new information to further understand the regulatory mechanism of the PLC-delta4 function. ..
  14. Hayama M, Okumura Y, Takahashi E, Shimabukuro A, Tamura M, Takeda N, et al. Identification and analysis of the promoter region of the type II transmembrane serine protease polyserase-1 and its transcript variants. Biol Chem. 2007;388:853-8 pubmed
  15. Yafe A, Shklover J, Weisman Shomer P, Bengal E, Fry M. Differential binding of quadruplex structures of muscle-specific genes regulatory sequences by MyoD, MRF4 and myogenin. Nucleic Acids Res. 2008;36:3916-25 pubmed publisher
    ..We speculate that the dissimilar interaction of MyoD and Myogenin with tetrahelical domains in muscle gene promoters may differently regulate their myogenic activities. ..
  16. Yan S, Zhou C, Lou X, Xiao Z, Zhu H, Wang Q, et al. PTTG overexpression promotes lymph node metastasis in human esophageal squamous cell carcinoma. Cancer Res. 2009;69:3283-90 pubmed publisher
    ..These findings elucidate the molecular mechanisms of PTTG overexpression in promoting tumor metastasis, whereby up-regulated PTTG modulates expression and secretion of metastasis-related factors to facilitate cell motility. ..
  17. Providence K, White L, Tang J, Gonclaves J, Staiano Coico L, Higgins P. Epithelial monolayer wounding stimulates binding of USF-1 to an E-box motif in the plasminogen activator inhibitor type 1 gene. J Cell Sci. 2002;115:3767-77 pubmed
    ..These data are the first to indicate that binding of USF-1 to its target motif can be induced by 'tissue' injury in vitro and implicate USF-1 as a transcriptional regulator of genes (e.g. PAI-1) involved in wound repair. ..
  18. Perrin L, Benassayag C, Morello D, Pradel J, Montagne J. Modulo is a target of Myc selectively required for growth of proliferative cells in Drosophila. Mech Dev. 2003;120:645-55 pubmed
    ..Taken together, our results indicate that mod does not possess the full spectrum of dMyc activities, but is required selectively in proliferative cells to sustain their growth and to maintain their specific size. ..
  19. Dole V, Smola H, Dooley S, Said H, Oldak M, Pfister H, et al. The adenoviral E1A oncoprotein activates the Smad7 promoter: requirement of a functional E-box. Int J Oncol. 2009;35:1493-8 pubmed
    ..In conclusion, these results unravel a novel mechanism of how the AdV E1A oncoprotein induces a cellular inhibitor of TGF-beta signalling...
  20. Hulf T, Bellosta P, Furrer M, Steiger D, Svensson D, Barbour A, et al. Whole-genome analysis reveals a strong positional bias of conserved dMyc-dependent E-boxes. Mol Cell Biol. 2005;25:3401-10 pubmed
    ..These observations raise the possibility that a subset of Myc targets share a distinct regulatory mechanism. ..
  21. Gadiraju S, Vyhlidal C, Leeder J, Rogan P. Genome-wide prediction, display and refinement of binding sites with information theory-based models. BMC Bioinformatics. 2003;4:38 pubmed
  22. Horikawa I, Cable P, Mazur S, Appella E, Afshari C, Barrett J. Downstream E-box-mediated regulation of the human telomerase reverse transcriptase (hTERT) gene transcription: evidence for an endogenous mechanism of transcriptional repression. Mol Biol Cell. 2002;13:2585-97 pubmed
    ..g., by an inactivation of the telomerase repressor gene on chromosome 3. ..
  23. Inlay M, Tian H, Lin T, Xu Y. Important roles for E protein binding sites within the immunoglobulin kappa chain intronic enhancer in activating Vkappa Jkappa rearrangement. J Exp Med. 2004;200:1205-11 pubmed
    ..Because E2A family proteins are the only known factors that bind to these E boxes, these findings provide unambiguous evidence that E2A is a key regulator of kappa rearrangement. ..
  24. Yamada M, Shida Y, Takahashi K, Tanioka T, Nakano Y, Tobe T, et al. Prg1 is regulated by the basic helix-loop-helix transcription factor Math2. J Neurochem. 2008;106:2375-84 pubmed publisher
    ..Our results suggest that Math2 directly regulates Prg1 expression and that the Math2-Prg1 cascade plays an important role in neurite outgrowth in PC12 cells. ..
  25. Cavadini G, Petrzilka S, Kohler P, Jud C, Tobler I, Birchler T, et al. TNF-alpha suppresses the expression of clock genes by interfering with E-box-mediated transcription. Proc Natl Acad Sci U S A. 2007;104:12843-8 pubmed
    ..We suggest that the increase of TNF-alpha and IL-1beta, as seen in infectious and autoimmune diseases, impairs clock gene functions and causes fatigue. ..
  26. Kim M, Kim J, Shin J, Suh M. The SebHLH transcription factor mediates trans-activation of the SeFAD2 gene promoter through binding to E- and G-box elements. Plant Mol Biol. 2007;64:453-66 pubmed
  27. Balakumaran B, Porrello A, Hsu D, Glover W, Foye A, Leung J, et al. MYC activity mitigates response to rapamycin in prostate cancer through eukaryotic initiation factor 4E-binding protein 1-mediated inhibition of autophagy. Cancer Res. 2009;69:7803-10 pubmed publisher
    ..Taken together, our findings suggest that MYC expression abrogates sensitivity to rapamycin through increased expression of 4EBP1 and reduced autophagy. ..
  28. Hamlett I, Draper J, Strouboulis J, Iborra F, Porcher C, Vyas P. Characterization of megakaryocyte GATA1-interacting proteins: the corepressor ETO2 and GATA1 interact to regulate terminal megakaryocyte maturation. Blood. 2008;112:2738-49 pubmed publisher
    ..Finally, as ETO2 expression is restricted to immature megakaryocytes, these data suggest that ETO2 directly represses inappropriate early expression of a subset of terminally expressed megakaryocyte genes by binding to GATA1 and SCL. ..
  29. Appelbaum L, Gothilf Y. Mechanism of pineal-specific gene expression: the role of E-box and photoreceptor conserved elements. Mol Cell Endocrinol. 2006;252:27-33 pubmed
    ..Therefore, the mechanism identified for zebrafish aanat2, or at least part of it, may apply to other photoreceptor-specific genes in zebrafish and other species. ..
  30. Sato F, Kawamoto T, Fujimoto K, Noshiro M, Honda K, Honma S, et al. Functional analysis of the basic helix-loop-helix transcription factor DEC1 in circadian regulation. Interaction with BMAL1. Eur J Biochem. 2004;271:4409-19 pubmed
    ..These findings suggest that the basic region of DEC1 participates in the transcriptional regulation through a protein-protein interaction with BMAL1 and DNA binding to the E-box. ..
  31. Woods S, Farrall A, Procko C, Whitelaw M. The bHLH/Per-Arnt-Sim transcription factor SIM2 regulates muscle transcript myomesin2 via a novel, non-canonical E-box sequence. Nucleic Acids Res. 2008;36:3716-27 pubmed publisher
    ..This is the first report of a direct SIM2/ARNT1 target gene with accompanying analysis of a functional response element. ..
  32. Cheng L, Li B, Tu H, Liu Q, Ran P. [Preliminary analysis of the 5'-flanking region of rat gamma-glutamylcysteine synthetase catalytic subunit gene]. Zhonghua Jie He He Hu Xi Za Zhi. 2005;28:164-8 pubmed
    ..A newly identified region -745 to -705 bp of GCLC gene, which can be bound by USF, is involved in negative gene regulation, suggesting that the interaction between E-box and USF can inhibit the expression of gamma-GCS. ..
  33. Leśniak W, Kuznicki J. Binding and functional characteristics of two E-box motifs within the S100A6 (calcyclin) gene promoter. J Cell Biochem. 2006;97:1017-24 pubmed
    ..Furthermore, we show that S100A6 gene promoter activity can be stimulated by palmitate and that mutation of the -283/-278 E-box sequence completely blocks this stimulation. ..
  34. Imanishi M, Nakamura A, Morisaki T, Futaki S. Positive and negative cooperativity of modularly assembled zinc fingers. Biochem Biophys Res Commun. 2009;387:440-3 pubmed publisher
    ..Our results indicate that not only a positive cooperativity but also a context-dependent reduction in the DNA binding activity can be induced by assembling zinc finger modules. ..
  35. Bismuth K, Maric D, Arnheiter H. MITF and cell proliferation: the role of alternative splice forms. Pigment Cell Res. 2005;18:349-59 pubmed
    ..The results suggest that one or several aminoterminal domains cooperate with the alternatively spliced hexapeptide to render MITF anti-proliferative in a way that does not depend on direct E box binding. ..
  36. Kanno R, Ogihara T, Igarashi Y, Tanaka Y, Smith S, Kojima I, et al. Activin A-induced expression of PAX4 in AR42J-B13 cells involves the increase in transactivation of E47/E12. Biochim Biophys Acta. 2006;1759:44-50 pubmed
    ..Our results suggest that activin A enhances PAX4 expression by enhanced transactivation of E47/E12 proteins and might result in a cumulative transactivation of the promoter. ..
  37. Li D, Niu Z, Yu W, Qian Y, Wang Q, Li Q, et al. SMYD1, the myogenic activator, is a direct target of serum response factor and myogenin. Nucleic Acids Res. 2009;37:7059-71 pubmed publisher
    ..Taken together, these studies demonstrated that SMYD1 is a key regulator of myogenic differentiation and acts as a downstream target of muscle regulatory factors, SRF and myogenin. ..
  38. Powell L, Deaton A, Wear M, Jarman A. Specificity of Atonal and Scute bHLH factors: analysis of cognate E box binding sites and the influence of Senseless. Genes Cells. 2008;13:915-29 pubmed publisher
    ..Moreover, the proneural cofactor, Senseless, can augment the function of Sc and Ato on their cognate E boxes and therefore may contribute to proneural specificity. ..
  39. Kajiwara M, Terada T, Asaka J, Aoki M, Katsura T, Ikai I, et al. Regulation of basal core promoter activity of human organic cation transporter 1 (OCT1/SLC22A1). Am J Physiol Gastrointest Liver Physiol. 2008;295:G1211-6 pubmed publisher
    ..These findings indicated that both USF1 and USF2 bind to an E-box sequence located in the OCT1 core promoter region and are required for the basal gene expression of this transporter. ..
  40. Chatterji B, Borlak J. A 2-DE MALDI-TOF study to identify disease regulated serum proteins in lung cancer of c-myc transgenic mice. Proteomics. 2009;9:1044-56 pubmed publisher
    ..Therefore, candidate biomarkers to differentiate between atypical adenomatous hyperplasias (AAH) and bronchiolo-alveolar carcinomas (BAC)/papillary adenocarcinomas (PLAC) can be proposed. ..
  41. Nakamura H, Tanimoto K, Hiyama K, Yunokawa M, Kawamoto T, Kato Y, et al. Human mismatch repair gene, MLH1, is transcriptionally repressed by the hypoxia-inducible transcription factors, DEC1 and DEC2. Oncogene. 2008;27:4200-9 pubmed publisher
    ..Hypoxia-induced DEC may impair MMR function through repression of MLH1 expression, possibly via the histone deacethylase-mediated mechanism in cancer cells. ..
  42. Dohadwala M, Yang S, Luo J, Sharma S, Batra R, Huang M, et al. Cyclooxygenase-2-dependent regulation of E-cadherin: prostaglandin E(2) induces transcriptional repressors ZEB1 and snail in non-small cell lung cancer. Cancer Res. 2006;66:5338-45 pubmed
    ..Thus, blocking PGE(2) production or activity may contribute to both prevention and treatment of NSCLC. ..
  43. Krizhanovsky V, Soreq L, Kliminski V, Ben Arie N. Math1 target genes are enriched with evolutionarily conserved clustered E-box binding sites. J Mol Neurosci. 2006;28:211-29 pubmed
    ..Our findings may be useful to the study of other bHLH transcription factors, many of which control the development of the nervous system. ..
  44. Liao C, Hsiao Y, Hsu C, Lin M, Wang J, Huang Y, et al. Transcriptionally mediated inhibition of telomerase of fungal immunomodulatory protein from Ganoderma tsugae in A549 human lung adenocarcinoma cell line. Mol Carcinog. 2006;45:220-9 pubmed
    ..Our findings provide new insight into both the anticancer function of reFIP-gts and the regulation of hTERT/telomerase expression, which may be valuable in the development of a promising chemopreventive agent. ..
  45. Kielbasa S, Gonze D, Herzel H. Measuring similarities between transcription factor binding sites. BMC Bioinformatics. 2005;6:237 pubmed
    ..Moreover, the application of the measures is illustrated by assigning E-box matrices of a SELEX experiment and of experimentally characterised binding sites of circadian clock genes to the Myc-Max cluster. ..
  46. Awasthi S, Sharma A, Wong K, Zhang J, Matlock E, Rogers L, et al. A human T-cell lymphotropic virus type 1 enhancer of Myc transforming potential stabilizes Myc-TIP60 transcriptional interactions. Mol Cell Biol. 2005;25:6178-98 pubmed
    ..Importantly, these results suggest that p30II functions as a novel retroviral modulator of Myc-TIP60-transforming interactions that may contribute to adult T-cell leukemogenesis. ..
  47. van der Stoep N, Quinten E, Marcondes Rezende M, van den Elsen P. E47, IRF-4, and PU.1 synergize to induce B-cell-specific activation of the class II transactivator promoter III (CIITA-PIII). Blood. 2004;104:2849-57 pubmed
    ..The finding that PU.1, IRF-4, and E47 play an important role in the B-cell-mediated activation of CIITA-PIII provides a link between antigen presentation functions and activation and differentiation events in B lymphocytes. ..
  48. Westerman B, Chhatta A, Poutsma A, van Vegchel T, Oudejans C. NEUROD1 acts in vitro as an upstream regulator of NEUROD2 in trophoblast cells. Biochim Biophys Acta. 2004;1676:96-103 pubmed
    ..This expression pattern, as well as the present transactivation results, might suggest the presence of a NEUROD differentiation cascade during first trimester human placental development. ..
  49. Seki K, Fujimori T, Savagner P, Hata A, Aikawa T, Ogata N, et al. Mouse Snail family transcription repressors regulate chondrocyte, extracellular matrix, type II collagen, and aggrecan. J Biol Chem. 2003;278:41862-70 pubmed
    ..Because type II collagen and aggrecan are major functional components of extracellular matrix in cartilage, these results suggest an important role for Snail-related transcription repressors during chondrocyte differentiation. ..
  50. Maleki S, Royer C, Hurlburt B. Analysis of the DNA-binding properties of MyoD, myogenin, and E12 by fluorescence anisotropy. Biochemistry. 2002;41:10888-94 pubmed
    ..The combination of differential affinity and cooperativity explains why the heterodimers are the active species in transcriptional regulation. ..
  51. Soucek L, Jucker R, Panacchia L, Ricordy R, Tatò F, Nasi S. Omomyc, a potential Myc dominant negative, enhances Myc-induced apoptosis. Cancer Res. 2002;62:3507-10 pubmed
    ..These findings suggest that Omomyc can selectively trigger apoptosis in cells overexpressing Myc, possibly through the transcriptional repression of specific genes. ..
  52. Murisier F, Beermann F. Genetics of pigment cells: lessons from the tyrosinase gene family. Histol Histopathol. 2006;21:567-78 pubmed publisher
    ..Thus, by using the tyrosinase gene family as a model, it is possible to define the transcription factor networks that govern pigment production in either melanocytes or RPE. ..
  53. Montagne M, Naud J, McDuff F, Lavigne P. Toward the elucidation of the structural determinants responsible for the molecular recognition between Mad1 and Max. Biochemistry. 2005;44:12860-9 pubmed
    ..K., and Burley, S. K. (2003) Cell 112, 193-205]. This clearly suggests that Asp 112 plays a crucial role in the molecular recognition between Max and Mad1. ..