TC element gene transcriptions

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Editor-In-Chief: Henry A. Hoff

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Baby bunny is at Floyd Lamb Park. Credit: Renee Grayson.{{free media}}

"The human TGF-β1 promoter region contains two binding sequences for AP-1, designated AP-1 box A (TGACTCT) and box B (TGTCTCA), which mediate the up-regulation of promoter activity after [High glucose] HG stimulation."[1]

Human genes

Gene ID: 7040 is TGFB1 transforming growth factor beta 1. "This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGFB family members. This encoded protein regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors including interferon gamma and tumor necrosis factor alpha. This gene is frequently upregulated in tumor cells, and mutations in this gene result in Camurati-Engelmann disease."[2]

Gene ID: 7042 is TGFB2 transforming growth factor beta 2. "This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. Disruption of the TGF-beta/SMAD pathway has been implicated in a variety of human cancers. A chromosomal translocation that includes this gene is associated with Peters' anomaly, a congenital defect of the anterior chamber of the eye. Mutations in this gene may be associated with Loeys-Dietz syndrome. This gene encodes multiple isoforms that may undergo similar proteolytic processing."[3]

  1. NP_001129071.1 transforming growth factor beta-2 proprotein isoform 1 precursor. "Transcript Variant: This variant (1) represents the longest transcript and encodes the longer isoform (1). This isoform (1) may undergo proteolytic processing similar to isoform 2."[3]
  2. NP_003229.1 transforming growth factor beta-2 proprotein isoform 2. "Transcript Variant: This variant (2) lacks an in-frame exon in the 5' coding region compared to variant 1. The resulting isoform (2) is shorter than isoform 1."[3]
  3. NR_138148.1 RNA Sequence. "Transcript Variant: This variant (3) lacks an internal exon and uses an alternate splice site in an internal exon compared to variant 1. This variant is represented as non-coding because the use of the 5'-most expected translational start codon renders the transcript a candidate for nonsense-mediated mRNA decay (NMD)."[3]
  4. NR_138149.1 RNA Sequence. "Transcript Variant: This variant (4) uses an alternate splice site in an internal exon compared to variant 1. This variant is represented as non-coding because the use of the 5'-most expected translational start codon renders the transcript a candidate for nonsense-mediated mRNA decay (NMD)."[3]

Gene ID: 7043 is TGFB3 transforming growth factor beta 3. "This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. This protein is involved in embryogenesis and cell differentiation, and may play a role in wound healing. Mutations in this gene are a cause of aortic aneurysms and dissections, as well as familial arrhythmogenic right ventricular dysplasia 1."[4]

  1. NP_003230.1 transforming growth factor beta-3 proprotein isoform 1 preproprotein. "Transcript Variant: This variant (1) represents the longest transcript and encodes the longer isoform (1). Both variants 1 and 2 encode the same isoform (1)."[4]
  2. NP_001316868.1 transforming growth factor beta-3 proprotein isoform 1 preproprotein. "Transcript Variant: This variant (2) differs in the 5' UTR compared to variant 1. Both variants 1 and 2 encode the same isoform (1)."[4]
  3. NP_001316867.1 transforming growth factor beta-3 proprotein isoform 2 precursor. "Transcript Variant: This variant (3) lacks several exons and its 3' terminal exon extends past a splice site that is used in variant 1. This results in an early stop codon and a novel 3' UTR compared to variant 1. The encoded isoform (2) has a shorter C-terminus than isoform 1."[4]

Gene ID: 7044 is LEFTY2 left-right determination factor 2 aka TGFB4. "This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate the mature protein, which plays a role in left-right asymmetry determination of organ systems during development. The protein may also play a role in endometrial bleeding. Mutations in this gene have been associated with left-right axis malformations, particularly in the heart and lungs. Some types of infertility have been associated with dysregulated expression of this gene in the endometrium. This gene is closely linked to both a related family member and a related pseudogene. This gene encodes multiple isoforms that may undergo similar proteolytic processing."[5]

  1. NP_001165896.1 left-right determination factor 2 isoform 2 precursor. "Transcript Variant: This variant (2) uses an alternate in-frame splice site in the coding region, compared to variant 1. This results in a shorter protein (isoform 2), compared to isoform 1. This isoform (2) lacks a portion of the mature peptide compared to isoform 1, but may undergo proteolytic processing similar to isoform 1."[5]
  2. NP_003231.2 left-right determination factor 2 isoform 1 preproprotein. "Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1)."[5]

TGFβ control elements

"Transforming growth factor beta (TGFβ) is implicated in the regulation of smooth muscle cell (SMC) differentiation. [A] novel TGFβ control element (TCE) [occurs] in the promoters of SMC differentiation marker genes including α SM actin and SM22α."[6]

The "promoters of multiple other SMC differentiation marker genes including SM22α and SM-MHC were also found to contain similar TCE regions [11]."[6]

The "α SM actin CArG element (CArG A) was required in combination with the TCE to coordinately regulate TGFβ-induced α SM actin expression in cultured cells [11]."[6]

TCE consensus sequences

The consensus sequence for the TCE in mouse and rat is 5'-GAGTGGGGCG-3' (-117) within the SM22α promoter which extends from -450 to +65 and includes two CArG transcription factors upstream of the TCE.[6]

In mouse and rat SM22α promoters there are 14 nts between the nearest upstream CArG and the TCE, specifically 5'-AGCCTGTGTGGAGT-3'.[6]

"The sequence of the TCE in the human c-myc promoter is [5'-GCGTGGGGGA-3']."[7]

TGF-β inhibitory elements

The "TGF-β inhibitory element (TIE) [is] in the rat transin/stromelysin promoter(12)."[7]

"Oprin was able to inhibit several snake venom metalloendopeptidases but failed to inhibit serine endopeptidases, MMPs or bacterial metalloendopeptidases [...]."[8]

TIE consensus sequences

5'-GAGTGGTGA-3'.[7]

Retinoblastoma control elements

"Robbins et al. (18) have reported that expression of pRB in mouse fibroblasts suppresses transcription of c-fos and have identified an element, termed the retinoblastoma control element (RCE), in the c-fos promoter necessary for this suppression. More recently, sequences homologous to the RCE have been identified in the TGF-β1, -β2, and -β3 promoters by Kim et al. (19)."[7]

"Kim et al. (19) also reported that sequences similar to the RCE are present in the human c-myc promoter".[7]

"Expression of some matrix metalloproteinases (MMPs) are regulated by cytokines and tumor promoters, namely tumor necrosis factor-𝛂 (TNF-𝛂), epidermal growth factor, interleukin-1, and 12-O-tetradecanoylphorbol-13-acetate (TPA) (15-20)."[9]

Binding site for NF𝛋B in humans (GGAATTCCCC) with a core of (GAATTC), Sp-1 (CCGCCCC), 12-O-tetradecanoylphorbol-13-acetate (TPA) responsive element (TRE) (TGAGTCA), and GC box (GGGCGG).[9]

"Angiotensin II (Ang II) up-regulates plasminogen-activator inhibitor type-1 (PAI-1) expression in mesangial cells to enhance extracellular matrix formation. The proximal promoter region (bp -87 to -45) of the human PAI-1 gene contains several potent binding sites for transcription factors [two phorbol-ester-response-element (TRE)-like sequences; D-box (-82 to -76) and P-box (-61 to 54), and one Sp1 binding site-like sequence, Sp1-box 1 (-72 to -67)]."[10]

RCE consensus sequences

Hypotheses

  1. No TCE occur in either A1BG promoter.
  2. A1BG has no TIE in either promoter.
  3. A1BG has no RCE in either promoter.

TCE samplings

Copying the consensus sequence for the TCE: GCGTGGGGGA and putting the sequence in "⌘F" finds no locations between ZNF497 and A1BG or no locations between ZSCAN22 and A1BG as can be found by the computer programs.

For the Basic programs testing consensus sequence GCGTGGGGGA (starting with SuccessablesTCE.bas) written to compare nucleotide sequences with the sequences on either the template strand (-), or coding strand (+), of the DNA, in the negative direction (-), or the positive direction (+), the programs are, are looking for, and found:

  1. negative strand, negative direction, looking for GCGTGGGGGA, 0.
  2. positive strand, negative direction, looking for GCGTGGGGGA, 0.
  3. positive strand, positive direction, looking for GCGTGGGGGA, 0.
  4. negative strand, positive direction, looking for GCGTGGGGGA, 0.
  5. complement, negative strand, negative direction, looking for CGCACCCCCT, 0.
  6. complement, positive strand, negative direction, looking for CGCACCCCCT, 0.
  7. complement, positive strand, positive direction, looking for CGCACCCCCT, 0.
  8. complement, negative strand, positive direction, looking for CGCACCCCCT, 0.
  9. inverse complement, negative strand, negative direction, looking for TCCCCCACGC, 0.
  10. inverse complement, positive strand, negative direction, looking for TCCCCCACGC, 0.
  11. inverse complement, positive strand, positive direction, looking for TCCCCCACGC, 0.
  12. inverse complement, negative strand, positive direction, looking for TCCCCCACGC, 0.
  13. inverse negative strand, negative direction, looking for AGGGGGTGCG, 0.
  14. inverse positive strand, negative direction, looking for AGGGGGTGCG, 0.
  15. inverse positive strand, positive direction, looking for AGGGGGTGCG, 0.
  16. inverse negative strand, positive direction, looking for AGGGGGTGCG, 0.

TIE samplings

3-GAGTGGTGA-5' was not found using "⌘F" to locate any consensus sequences.

For the Basic programs testing consensus sequence 3'-GAGTGGTGA-5' (starting with SuccessablesAbox.bas) written to compare nucleotide sequences with the sequences on either the template strand (-), or coding strand (+), of the DNA, in the negative direction (-), or the positive direction (+), the programs are, are looking for, and found:

  1. negative strand in the negative direction (from ZSCAN22 to A1BG) is SuccessablesTIE--.bas, looking for 3'-GAGTGGTGA-5', 0.
  2. negative strand in the positive direction (from ZNF497 to A1BG) is SuccessablesTIE-+.bas, looking for 3'-GAGTGGTGA-5', 0.
  3. positive strand in the negative direction (from ZSCAN22 to A1BG) is SuccessablesTIE+-.bas, looking for 3'-GAGTGGTGA-5', 0.
  4. positive strand in the positive direction (from ZNF497 to A1BG) is SuccessablesTIE++.bas, looking for 3'-GAGTGGTGA-5', 0.
  5. complement, negative strand, negative direction is SuccessablesTIEc--.bas, looking for 3'-CTCACCACT-5', 0.
  6. complement, negative strand, positive direction is SuccessablesTIEc-+.bas, looking for 3'-CTCACCACT-5', 0.
  7. complement, positive strand, negative direction is SuccessablesTIEc+-.bas, looking for 3'-CTCACCACT-5', 0.
  8. complement, positive strand, positive direction is SuccessablesTIEc++.bas, looking for 3'-CTCACCACT-5', 0.
  9. inverse complement, negative strand, negative direction is SuccessablesTIEci--.bas, looking for 3'-TCACCACTC-5', 0.
  10. inverse complement, negative strand, positive direction is SuccessablesTIEci-+.bas, looking for 3'-TCACCACTC-5', 0.
  11. inverse complement, positive strand, negative direction is SuccessablesTIEci+-.bas, looking for 3'-TCACCACTC-5', 0.
  12. inverse complement, positive strand, positive direction is SuccessablesTIEci++.bas, looking for 3'-TCACCACTC-5', 0.
  13. inverse negative strand, negative direction is SuccessablesTIEi--.bas, looking for 3'-AGTGGTGAG-5', 0.
  14. inverse negative strand, positive direction is SuccessablesTIEi-+.bas, looking for 3'-AGTGGTGAG-5', 0.
  15. inverse positive strand, negative direction is SuccessablesTIEi+-.bas, looking for 3'-AGTGGTGAG-5', 0.
  16. inverse positive strand, positive direction is SuccessablesTIEi++.bas, looking for 3'-AGTGGTGAG-5', 0.

GT box consensus sequences

Main article: Consensus sequence gene transcriptions

Expression "of v-Src induces the synthesis of MMP-9, which is mediated by alterations in activity of binding factors for the AP-1 site and the sequence motif GGGGTGGGG (GT box). This GT box is homologous to the so-called retinoblastoma (Rb) control element (RCE) (29,30), and Rb can produce an anti-oncogene or tumor suppressor gene product (31-38) which is involved in regulating transcription of certain genes."[9]

"Comparison of the sequence of the newly cloned mouse MMP-9 promoter region with our previous human isolate revealed that [...] four units of GGGG(T/A)GGGG sequence (GT box) were conserved between the two species."[9]

"The methylation-interference experiment demonstrated that human recombinant Sp1 bound to the so-called GT box (TGGGTGGGGCT, -78 to -69), which contains the Sp1-box 1."[10]

GT box (Sato) samplings

Copying the apparent consensus sequence for the RCE, GT box, (GGGGTGGGG) and putting it in "⌘F" finds none located between ZSCAN22 or between ZNF497 and A1BG as can be found by the computer programs. However, RCE (GGGGAGGGG) finds none located between ZSCAN22 and one between ZNF497 and A1BG.

For the Basic programs testing consensus sequence GGGG(T/A)GGGG (starting with SuccessablesGTbox.bas) written to compare nucleotide sequences with the sequences on either the template strand (-), or coding strand (+), of the DNA, in the negative direction (-), or the positive direction (+), the programs are, are looking for, and found:

  1. negative strand, negative direction, looking for GGGG(A/T)GGGG, 0.
  2. negative strand, positive direction, looking for GGGG(A/T)GGGG, 1, GGGGAGGGG at 2291, and complement.
  3. positive strand, negative direction, looking for GGGG(A/T)GGGG, 0.
  4. positive strand, positive direction, looking for GGGG(A/T)GGGG, 0.
  5. inverse complement, negative strand, negative direction, looking for CCCC(A/T)CCCC, 0.
  6. inverse complement, negative strand, positive direction, looking for CCCC(A/T)CCCC, 0.
  7. inverse complement, positive strand, negative direction, looking for CCCC(A/T)CCCC, 0.
  8. inverse complement, positive strand, positive direction, looking for CCCC(A/T)CCCC, 1, CCCCTCCCC at 2291.

GT box (Sato) positive direction (4050-1) distal promoters

  1. Negative strand, positive direction: GGGGAGGGG at 2291.

GT box random dataset samplings

  1. GTboxr0: 0.
  2. GTboxr1: 0.
  3. GTboxr2: 0.
  4. GTboxr3: 0.
  5. GTboxr4: 0.
  6. GTboxr5: 0.
  7. GTboxr6: 0.
  8. GTboxr7: 0.
  9. GTboxr8: 0.
  10. GTboxr9: 0.

GT box analysis and results

Main article: Complex locus A1BG and ZNF497 § GT boxes (Sato)

"Comparison of the sequence of the newly cloned mouse MMP-9 promoter region with our previous human isolate revealed that [...] four units of GGGG(T/A)GGGG sequence (GT box) were conserved between the two species."[9]

Reals or randoms Promoters direction Numbers Strands Occurrences Averages (± 0.1)
Reals UTR negative 0 2 0 0
Randoms UTR arbitrary negative 0 10 0 0
Randoms UTR alternate negative 0 10 0 0
Reals Core negative 0 2 0 0
Randoms Core arbitrary negative 0 10 0 0
Randoms Core alternate negative 0 10 0 0
Reals Core positive 0 2 0 0
Randoms Core arbitrary positive 0 10 0 0
Randoms Core alternate positive 0 10 0 0
Reals Proximal negative 0 2 0 0
Randoms Proximal arbitrary negative 0 10 0 0
Randoms Proximal alternate negative 0 10 0 0
Reals Proximal positive 0 2 0 0
Randoms Proximal arbitrary positive 0 10 0 0
Randoms Proximal alternate positive 0 10 0 0
Reals Distal negative 0 2 0 0
Randoms Distal arbitrary negative 0 10 0 0
Randoms Distal alternate negative 0 10 0 0
Reals Distal positive 1 2 0.5 0.5 ± 0.5 (-+1,++0)
Randoms Distal arbitrary positive 0 10 0 0
Randoms Distal alternate positive 0 10 0 0

Comparison:

The occurrences of the real GT box are larger than the randoms. This suggests that the real GT box is likely active or activable.

GT box (Motojima) samplings

Main article: Model samplings

Copying the apparent consensus sequence for the GT box (TGGGTGGGGCT) and putting it in "⌘F" finds none located between ZSCAN22 or between ZNF497 and A1BG as can be found by the computer programs.

For the Basic programs testing consensus sequence TGGGTGGGGCT (starting with SuccessablesGTMo.bas) written to compare nucleotide sequences with the sequences on either the template strand (-), or coding strand (+), of the DNA, in the negative direction (-), or the positive direction (+), the programs are, are looking for, and found:

  1. negative strand, negative direction, looking for TGGGTGGGGCT, 0.
  2. negative strand, positive direction, looking for TGGGTGGGGCT, 0.
  3. positive strand, negative direction, looking for TGGGTGGGGCT, 0.
  4. positive strand, positive direction, looking for TGGGTGGGGCT, 0.
  5. complement, negative strand, negative direction, looking for ACCCACCCCGA, 0.
  6. complement, negative strand, positive direction, looking for ACCCACCCCGA, 0.
  7. complement, positive strand, negative direction, looking for ACCCACCCCGA, 0.
  8. complement, positive strand, positive direction, looking for ACCCACCCCGA, 0.
  9. inverse complement, negative strand, negative direction, looking for AGCCCCACCCA, 0.
  10. inverse complement, negative strand, positive direction, looking for AGCCCCACCCA, 0.
  11. inverse complement, positive strand, negative direction, looking for AGCCCCACCCA, 0.
  12. inverse complement, positive strand, positive direction, looking for AGCCCCACCCA, 0.
  13. inverse negative strand, negative direction, looking for TCGGGGTGGGT, 0.
  14. inverse negative strand, positive direction, looking for TCGGGGTGGGT, 0.
  15. inverse positive strand, negative direction, looking for TCGGGGTGGGT, 0.
  16. inverse positive strand, positive direction, looking for TCGGGGTGGGT, 0.

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

References

  1. ↑ Keiko Kokoroishi, Ayumu Nakashima, Shigehiro Doi, Toshinori Ueno, Toshiki Doi, Yukio Yokoyama, Kiyomasa Honda, Masami Kanawa, Yukio Kato, Nobuoki Kohno & Takao Masaki (28 May 2015). "High glucose promotes TGF-β1 production by inducing FOS expression in human peritoneal mesothelial cells". Clinical and Experimental Nephrology. 20: 30–8. doi:10.1007/s10157-015-1128-9. Retrieved 14 August 2020.
  2. ↑ RefSeq (August 2016). "TGFB1 transforming growth factor beta 1 [ Homo sapiens (human) ]". 8600 Rockville Pike, Bethesda MD, 20894 USA: National Center for Biotechnology Information, U.S. National Library of Medicine. Retrieved 30 January 2020.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 RefSeq (August 2016). "TGFB2 transforming growth factor beta 2 [ Homo sapiens (human) ]". 8600 Rockville Pike, Bethesda MD, 20894 USA: National Center for Biotechnology Information, U.S. National Library of Medicine. Retrieved 30 January 2020.
  4. ↑ 4.0 4.1 4.2 4.3 RefSeq (August 2016). "TGFB3 transforming growth factor beta 3 [ Homo sapiens (human) ]". 8600 Rockville Pike, Bethesda MD, 20894 USA: National Center for Biotechnology Information, U.S. National Library of Medicine. Retrieved 30 January 2020.
  5. ↑ 5.0 5.1 5.2 RefSeq (August 2016). "LEFTY2 left-right determination factor 2 [ Homo sapiens (human) ]". 8600 Rockville Pike, Bethesda MD, 20894 USA: National Center for Biotechnology Information, U.S. National Library of Medicine. Retrieved 30 January 2020.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Paul J. Adam, Christopher P. Regan, Martina B. Hautmann, Gary K. Owens (August 22, 2000). "Positive and Negative Acting Krüppel-like Transcription Factors Bind a Transforming Growth Factor Beta Control Element Required for Expression of the Smooth Muscle Cell Differentiation Marker SM22α In Vivo" (PDF). Journal of Biological Chemistry. 275 (48): 37798–37806. doi:10.1074/jbc.M006323200. Retrieved 5 December 2018.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 Jennifer A. Pietenpol, Karl Munger, Peter M. Howley, Roland W. Stein and Harold L. Moses (November 15, 1991). "Factor-binding element in the human c-myc promoter involved in transcriptional regulation by transforming growth factor β1 and by the retinoblastoma gene product" (PDF). Proceedings of the National Academy of Sciences USA. 88 (22): 10227–10231. doi:10.1073/pnas.88.22.10227. Retrieved 5 December 2018.
  8. ↑ Bastos, Viviane A., Francisco Gomes-Neto, Jonas Perales, Ana Gisele C. Neves-Ferreira, and Richard H. Valente. 2016. "Natural Inhibitors of Snake Venom Metalloendopeptidases: History and Current Challenges" Toxins 8, no. 9: 250. https://doi.org/10.3390/toxins8090250.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 Hiroshi Sato, Megumi Kita, and Motoharu Seiki (5 November 1993). "v-Src Activates the Expression of 92-kDa Type IV Collagenase Gene through the AP-1 Site and the GT Box Homologous to Retinoblastoma Control Elements" (PDF). The Journal of Biological Chemistry. 268 (31): 23460–8. PMID 8226872. Retrieved 13 August 2020.
  10. ↑ 10.0 10.1 Masaru Motojima, Takao Ando and Toshimasa Yoshioka (10 July 2000). "Sp1-like activity mediates angiotensin-II-induced plasminogen-activator inhibitor type-1 (PAI-1) gene expression in mesangial cells" (PDF). Biomedical Journal. 349 (2): 435–441. doi:10.1042/0264-6021:3490435. PMID 10880342. Retrieved 13 August 2020.

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