Upstream response element gene transcriptions

Editor-In-Chief: Henry A. Hoff

"Apolipoprotein E (apoE)1 is a major component of various classes of plasma lipoproteins. It is a single-chain polypeptide of 299 amino acids, which plays a prominent role in transport and metabolism of plasma cholesterol and triglycerides, resulting from its ability to interact with lipoprotein receptors (1). The amino acid sequence of the human protein presents two polymorphic sites that generate three isoforms (apoE2, apoE3, and apoE4)."

"URE1 and URE3, upstream response elements 1 and 3 (24, 28)" occur within -163 to -124 and -113 to -80, respectively, and a TATA box within -38 to about -30 nts "of the proximal APOE promoter".

An "unidentified protein was reported to bind to URE3 between -89 and -101 (28)."

"To identify specific sequences in the 5'-flanking region that are significant for human apoE gene expression, portions of the 5‘ ends of this region were progressively deleted by Bal31 nuclease treatment. [...] In both CHO and HepG2 cells, deletion of the 268 nucleotides between -651 and -383, which contains part of an AluI sequence, had little effect on apoE promoter-directed CAT activity. Deletion of the region between nucleotides -383 and -212 resulted in almost a 2-fold reduction in CAT activity. This region contains two types of directly repeated elements: 5‘-TCCAGAT-3’ (-355 to -349, -335 to -329, and -268 to -262) and 5’-CAGGAAAGGA-3’ (-312 to -303 and -296 to -287). In addition, this region contains the hexanucleotide core sequences of an Spl protein binding "GC box" (-279 to -274) (36), but the identities of the neighboring nucleotides indicate that it may be a low affinity binding site (37). Deletion of the sequence between nucleotides -212 and -81 resulted in about a 4-fold reduction in CAT activity in both cell types. The removal of the region between nucleotides -81 and -39 resulted in another 2.5-4-fold reduction in promoter activity. Since this region contains two GC boxes, these results suggest that one or both GC boxes are functional components of the apoE promoter complex. Deletion of the region from nucleotides -39 to -14, which contains a consensus TATA box element, results in an additional 6- to 10-fold decrease in activity. In summary, the results from these deletion studies with the chimeric CAT gene suggest that, in addition to the TATA box in the proximal 383 nucleotides of the 5’-flanking region of human apoE gene at least three different domains, possibly containing several elements, are involved in the regulation of its transcription."

There "are three elements with enhancer-like properties located within this 1-kb fragment. One element, termed upstream regulatory element 2 (URE2), is located between residues -366 and -246. Another element, termed upstream regulatory element 1 (UREl), was found in a fragment located between residues -246 and -81; UREl is located within a 69-bp segment between residues -193 and -124 of this fragment. The third element, termed intron regulatory element1 (IREl), was found within the first intron and is located in a 219-bp segment between residues +44 and +262. These three elements had promoter-enhancing activity in both orientations."

URE1 is apparently 5'-ACCTCTATGCCCCACCTCCTTC-3' or contained in it between -193 to -124. URE2 is apparently contained in -366 to -246.

URE1 may be 5‘-AGGAG(G/C)(T/G)GGGG(C/T)-3'.

"The sequence of the URE1 protein binding region [...] contains inverted repeated sequences (-164 to -159, -152 to -147, 5‘-ACCTCTATGCCCCACCTCCTTC-3’)."

Upstream response or regulatory elements

"In the [gonadotropin] 􏰁𝛂-gene, two identical repeats of a consensus cAMP response element (CRE) are located between -􏰇146 and -􏰇111 bp of the promoter (10–12). These CREs bind cAMP response element-binding protein (12–14) along with other members of the B-Zip family of transcription factors (15, 16). An adjacent element, termed the upstream response element (URE, -􏰇180 to 􏰇-151), also contributes to basal expression and appears to contribute to placenta-specific expression of the 􏰁𝛂-promoter (12, 13, 17–20). The URE contains three overlapping protein binding sites referred to as the trophoblast-specific element (TSE, or URE2 (􏰇-187 to -􏰇159)) (12, 13, 18, 21), downstream domain (-􏰇172 to -􏰇151) (13, 19), and GATA (𝛂􏰁-ACT, URE1) (-􏰇165 to -􏰇140) (22). Protein binding to the TSE and downstream domain are mutually exclusive (13, 19)."

"In the case of the 𝛂􏰁-gene, modifications in the CRE sequence and in adjacent upstream regulatory elements appear to account for the ability of the 𝛂􏰁-gene to be expressed in the placenta as well as in the pituitary gland (17, 18)." The term upstream regulatory element refers to the general situation while upstream response element refers to a specific element.

"The transcription factor Nrf2 (nuclear factor erythroid 2 p45‐related factor 2) regulates the expression of genes involved in cellular protection against damage by oxidants, electrophiles, and inflammatory agents, and in the maintenance of mitochondrial function, cellular redox, and protein homeostasis [1]. Nrf2 protein comprises seven functional domains termed Nrf2‐ECH homology (Neh) 1–7 domains [...]."

"At homeostatic conditions, Nrf2 is a short‐lived protein. Under stress conditions, Nrf2 is stabilized and translocates to the nucleus, where it binds (as a heterodimer with a member of the small Maf family of transcription factors) to the ARE/EpRE sequences in the promoter of its target genes, and activates their transcription. Nrf2 targets include genes that encode detoxification, antioxidant, and anti‐inflammatory proteins as well as proteins involved in the regulation of autophagy and clearance of damaged proteins, such as proteasomal subunits [9-11]."

"Neh1 is responsible for the formation of a heterodimer with small musculoaponeurotic fibrosarcoma (sMaf) proteins, and mediates binding to antioxidant/electrophile response element (ARE/EpRE) sequences in the promoter regions of Nrf2 target genes."

"A meta‐analysis of PD and AD microarray datasets identified 31 common downregulated genes containing the ARE/EpRE consensus sequence in their promoters, in addition to increased levels of Nrf2 [27]."

"Nrf2 binds an upstream response element in the frataxin locus, and the anesthetic dyclonine has been shown to activate Nrf2, increase the mRNA and protein levels of frataxin and rescue frataxin‐dependent enzyme deficiencies in the iron‐sulfur enzymes aconitase and succinate dehydrogenase [54]."

The "Nrf2-sMaf heterodimer recognizes DNA sequences referred to as the antioxidant/electrophile responsive element (ARE/EpRE)". "We have compared these binding sequences and found that they show a common consensus sequence, 5′-(A/G)TGA(G/C)nnnGC-3′, but these recognition elements are partially distinct from the element bound by Maf homodimers."

Large "and small Maf proteins are able to form homodimers that recognize the Maf recognition element (MARE)."

The "CsMBE sequence shares substantial overlap with that of the Maf recognition element (MARE), a palindromic motif 5′-TGCTGA(G/C)TCAGCA-3′ (underline shows overlapping sequence with CsMBE) that binds homodimers of large Maf proteins".

"sMaf proteins can form homodimers with themselves and bind to the Maf recognition element (MARE: TGCTGACTCAGCA)".

"Various stress signals activate these transcription factors which further get associated with the heat shock-responsive element (HSE), a greatly conserved upstream response element, located in the promoter of heat shock genes".

"In plants, the optimal HSE core consensus sequence was shown to be 5'-aGAAg-3'[54]. At least three units, resulting in 5'-nGAAnnTTCnnGAAn-3', are efficient for the HSF binding [50]."

Acknowledgements

The content on this page was first contributed by: Henry A. Hoff.

Initial content for this page in some instances came from Wikiversity.

See also

• A1BG gene transcriptions
• Apolipoprotein E
• TATA box gene transcriptions