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"The most dramatic impact on immunoglobulin gene enhancer activity was observed upon mutation of sites that contain an E2-box motif (G/ACAGNTGN)."[1]

"The E box sites that are most important are those of the E2 box class (GCAGXTGG/T). Two E2 box sites are present in the immunoglobulin heavy chain gene enhancer, p.E2 and /~E5, and one is present in the kappa enhancer, designated KE2 [29-31]."[2]



"Transcriptional downregulation of E-cadherin appears to be an important event in the progression of various epithelial tumors. SIP1 (ZEB-2) is a Smad-interacting, multi-zinc finger protein that shows specific DNA binding activity. [Expression] of wild-type but not of mutated SIP1 downregulates mammalian E-cadherin transcription via binding to both conserved E2 boxes of the minimal E-cadherin promoter."[3]

"Analysis of mouse and human E-cadherin promoters revealed a conserved modular structure with positive regulatory elements including two E2 boxes (CACCTG) with a potential repressor role Behrens et al. 1991, Giroldi et al. 1997."[3]

"The two E2 boxes in the mouse and human E-cadherin promoter sequences were demonstrated to play a crucial role in the epithelial-specific expression of E-cadherin Behrens et al. 1991, Giroldi et al. 1997. Mutation of these sequence elements results in upregulation of the E-cadherin promoter in dedifferentiated cancer cells, whereas the wild-type promoter shows low activity in such cells. Recently, it was shown that the zinc finger transcriptional repressor Snail can downregulate E-cadherin by binding to the E boxes in the E-cadherin promoter Batlle et al. 2000, Cano et al. 2000. Human Snail belongs to a family of zinc finger proteins, which contain four or five zinc finger domains of the C2H2 type at their C-terminal end. These zinc fingers bind to the CANNTG sequence in E box motifs."[3]

"δEF1 and SIP1 have been shown to bind spaced CACCT DNA sequences, including E2 boxes (CACCTG), by their zinc finger clusters (Remacle et al., 1999)."[3]

"To address the specificity of SIP1 action, mutagenesis of the E-cadherin promoter in either its upstream E2 box 1 (−75) or its downstream E2 box 3 (−25), or in both E2 boxes was performed [...]."[3]

Wild-type "SIP1 represses the E-cadherin promoter, likely through binding via both zinc finger clusters to spaced E2 boxes as demonstrated previously (Remacle et al., 1999) and confirmed here by a DNA-mediated pull-down assay of SIP1 protein [...]. Wild-type but not mutated SIP1 from transfected human cells could be efficiently precipitated by biotinylated E-cadherin promoter oligonucleotides, comprising two wild-type E2 box sequences. Mutation of the E2 boxes resulted in the loss of SIP1 binding."[3]

Human E2 boxes are E2-box 1 (GCAGGTGA), E2-box 2 (TGGCCGGC) and E2-box 3 (TCACCTGG).[3]

"Alignment of the E-cadherin promoter sequences of dog, mouse, and man. Conserved regulatory elements are indicated: E2 boxes 1 and 3, CCAAT box, and GC box. The E2 box 2 has been described as part of a palindromic E-pal sequence in the mouse E-cadherin promoter (Behrens et al., 1991), but is conserved neither in canine nor in human sequences."[3]


"Snail family genes encode zinc finger-containing proteins that function primarily as transcriptional repressors [1,2]. To date, three members of the Snail gene family have been described in vertebrates: Snai1 (also known as Snail), Snai2 (Slug) and Snai3 (Smuc). Snail family proteins possess a highly conserved carboxy-terminal region, containing four or five Cys2-His2 (C2H2)-type zinc finger regions and a more divergent amino-terminus that contains the evolutionarily conserved SNAG domain. The zinc finger regions are sequence-specific DNA-binding domains that bind E2-box sequences (CAGGTG and CACCTG). Both the SNAI1 and SNAI2 proteins recruit other proteins, such as histone deacetylase-1 (HDAC-1), to the E2 boxes of target genes to form a transcriptional repression complex that suppresses the transcription of Snail target genes [3,4]."[4]

"We searched the regions from −2500 bp to +500 bp of the Snai1 and Snai2 genes for E2 box sequences (CACCTG and CAGGTG), and identified eleven in the Snai1 promoter region [...] and five in the Snai2 promoter region [...]."[4]

"ChIP assays demonstrated binding of the SNAI1 and SNAI2 proteins to a subset of E2 boxes in both their own and each other’s promoter regulatory regions [...]. The SNAI2 protein bound to the Snai1 promoter region at sites 4, 7 and 8 [...], whereas the SNAI1 protein bound to its own promoter region at sites 2, 3, 4, 7, and 8 [...]. Conversely, the SNAI1 protein bound to the Snai2 promoter region at site 5 [...], whereas the SNAI2 protein bound its own promoter region at site 3, 4 and 5 [...]."[4]

See alsoEdit


  1. Cornelis Murre and David Baltimore (1992). The Helix-Loop-Helix Motif: Structure and Function, In: Transcriptional Regulation. 22B. Cold Spring Harbor Laboratory Press. pp. 861-79. doi:10.1101/087969425.22B.861. Retrieved 2017-02-08. 
  2. Cornelis Murre, Gretchen Bain, Marc A. van Dijk, Isaac Engel, Beth A. Furnari, Mark E. Massari, James R. Matthews, Melanie W. Quong, Richard R. Rivera, Maarten H. Stuiver (June 1994). "Structure and function of helix-loop-helix proteins". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 1218 (2): 129-35. Retrieved 2017-02-08. 
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Joke Comijn, Geert Berx, Petra Vermassen, Kristin Verschueren, Leo van Grunsven, Erik Bruyneel, Marc Mareel, Danny Huylebroeck, Frans van Roy (June 2001). "The Two-Handed E Box Binding Zinc Finger Protein SIP1 Downregulates E-Cadherin and Induces Invasion". Molecular Cell 7 (6): 1267-78. doi:10.1016/S1097-2765(01)00260-X. Retrieved 11 January 2019. 
  4. 4.0 4.1 4.2 Ying Chen and Thomas Gridley (2013 June 7). "The Snai1 and Snai2 proteins occupy their own and each other’s promoter during chondrogenesis". Biochem Biophys Res Commun. 435 (3): 356–360. doi:10.1016/j.bbrc.2013.04.086. Retrieved 12 January 2019. 

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