M box gene transcriptions

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Editor-In-Chief: Henry A. Hoff

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"In melanocytes and in melanoma cells, cyclic AMP (cAMP)-elevating agents stimulate melanogenesis and increase the transcription of tyrosinase, the rate-limiting enzyme in melanin synthesis. However, two other enzymes, tyrosinase-related protein 1 (TRP1) and TRP2, are required for a normal melanization process leading to eumelanin synthesis. In B16 melanoma cells, we demonstrated that stimulation of melanogenesis by cAMP-elevating agents results in an increase in tyrosinase, TRP1, and TRP2 expression. cAMP, through a cAMP-dependent protein kinase pathway, stimulates TRP1 and TRP2 promoter activities in both B16 mouse melanoma cells and normal human melanocytes. Regulation of the TRP1 and TRP2 promoters by cAMP involves a M box and an E box."[1]

"[M]icrophthalmia, a basic helix-loop-helix transcription factor, strongly stimulates the transcriptional activities of the TRP1 and TRP2 promoters, mainly through binding to the M boxes."[1]

"In mammals, pigmentation results from the synthesis and distribution of melanin in the skin, hair bulbs, and eyes. Melanin synthesis (melanogenesis) takes place in the melanocyte after differentiation of the nonpigmented precursor, the melanoblast (27). Three melanocyte-specific enzymes, tyrosinase, tyrosinase-related protein 1 (TRP1), and TRP2, are involved in this enzymatic process that converts tyrosine to melanin pigments. Although these proteins have similar structures and features, they are expressed by different genes and possess distinct enzymatic activities. Tyrosinase, encoded by the albino locus of the mouse, catalyzes the conversion of tyrosine to 3,4-dihydroxyphenylalanine (DOPA) and of DOPA to DOPA quinone (14, 25, 31). TRP2, encoded by the mouse slaty locus, possesses a Dopachrome tautomerase activity, converting the Dopachrome to 5,6-dihydroxyindole-2-carboxylic acid (DHICA) (3, 19, 42). TRP1, which has been mapped in mouse to the brown locus, catalyzes the oxidation of DHICA to indole-5,6-quinone-2-carboxylic acid (21, 24)."[1]

"In the TRP1 promoter, the M box (GTCATGTGCT) [is] located between bp −44 and −33 upstream from the initiation start site [...] and the E box (CAAGTG) [is] located between bp −238 and −233 [...] In the TRP2 promoter, the M box (GTCATGTGCT) [is] located between bp −135 and −129 upstream from the initiation start site [...] the E box (CACATG) [is] between bp −346 and −340 [and] the cAMP response element (CRE; TGAGGTCA) [is] located between bp −239 and −232 [...]."[1]

The "regulation of TRP1 gene expression by PKA in B16 melanoma cells involves the M box just upstream of the TATA box."[1]

Human genes

Main article: Human genes

Gene ID: 1638 is DCT dopachrome tautomerase, aka TRP-2; TYRP2.[2]

  1. NP_001123361.1 L-dopachrome tautomerase isoform 2 precursor: "Transcript Variant: This variant (2) includes two alternate in-frame exons and is predicted to encode a slightly longer protein isoform (2) compared to isoform 1."[2]
  2. NP_001309111.1 L-dopachrome tautomerase isoform 3.[2]
  3. NP_001309112.1 L-dopachrome tautomerase isoform 3.[2]
  4. NP_001309113.1 L-dopachrome tautomerase isoform 3.[2]
  5. NP_001309114.1 L-dopachrome tautomerase isoform 3.[2]
  6. NP_001309115.1 L-dopachrome tautomerase isoform 4.[2]
  7. NP_001913.2 L-dopachrome tautomerase isoform 1 precursor: "Transcript Variant: This variant (1) represents the more abundant transcript."[2]

Gene ID: 7306 is TYRP1 tyrosinase related protein 1: "This gene encodes a melanosomal enzyme that belongs to the tyrosinase family and plays an important role in the melanin biosynthetic pathway. Defects in this gene are the cause of rufous oculocutaneous albinism and oculocutaneous albinism type III."[3]

Consensus sequences

Main article: Consensus sequence gene transcriptions

"Tyrosinase and TRP1 promoters share an 11-bp motif (AGTCATGTGCT) termed the M box located upstream of the TATA box. This motif binds microphthalmia, a basic helix-loop-helix transcription factor that increases tyrosinase and TRP1 promoter activities, thereby playing a key role in the tissue-specific expression of these genes (11, 29, 40). In the TRP2 promoter, a homologous sequence (GTCATGTGCT) is also found upstream of the TATA box (41)."[1]

The M box consensus sequence GTCATGTGCT[1] does not occur on either side of A1BG. The random datasets had only one occurrence GTCATGTGCT at 1977 in the distal promoter.

M-box consensus sequence is GGTCATGTGCT.[4] This contains the core consensus sequence GTCATGTGCT.[1]

"The conserved region contains a consensus M-box element (TCACATGA) for binding of MITF. This MITF binding site is aligned and conserved between at least 11 different species [...]. The clear conservation of these elements suggests that gpnmb has similar regulation in all mammals."[5]

M box (Bertolotto) samplings

Main article: Model samplings

Copying a responsive elements consensus sequence GTCATGTGCT and putting the sequence in "⌘F" finds none between ZNF497 and A1BG or none between ZSCAN22 and A1BG as can be found by the computer programs.

For the Basic programs testing consensus sequence GTCATGTGCT (starting with SuccessablesMbox.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 GTCATGTGCT, 0.
  2. positive strand, negative direction, looking for GTCATGTGCT, 0.
  3. positive strand, positive direction, looking for GTCATGTGCT, 0.
  4. negative strand, positive direction, looking for GTCATGTGCT, 0.
  5. inverse complement, negative strand, negative direction, looking for AGCACATGAC, 0.
  6. inverse complement, positive strand, negative direction, looking for AGCACATGAC, 0.
  7. inverse complement, positive strand, positive direction, looking for AGCACATGAC, 0.
  8. inverse complement, negative strand, positive direction, looking for AGCACATGAC, 0.

Bertolotto random dataset samplings

  1. Mboxr0: 0.
  2. Mboxr1: 0.
  3. Mboxr2: 0.
  4. Mboxr3: 0.
  5. Mboxr4: 0.
  6. Mboxr5: 0.
  7. Mboxr6: 0.
  8. Mboxr7: 0.
  9. Mboxr8: 0.
  10. Mboxr9: 1, GTCATGTGCT at 1977.
  11. Mboxr0ci: 0.
  12. Mboxr1ci: 0.
  13. Mboxr2ci: 0.
  14. Mboxr3ci: 0.
  15. Mboxr4ci: 0.
  16. Mboxr5ci: 0.
  17. Mboxr6ci: 0.
  18. Mboxr7ci: 0.
  19. Mboxr8ci: 0.
  20. Mboxr9ci: 0.

Mboxr distal promoters

Main article: Distal promoter gene transcriptions
  1. Mboxr9: GTCATGTGCT at 1977.

M-box (Hoek) samplings

Main article: Model samplings

Copying a responsive elements consensus sequence (T/N)CA(C/T)(A/G)TG(A/N) and putting the sequence in "⌘F" finds none between ZNF497 and A1BG or none between ZSCAN22 and A1BG as can be found by the computer programs.

For the Basic programs testing consensus sequence (T/N)CA(C/T)(A/G)TG(A/N) (starting with SuccessablesMHbox.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 (T/N)CA(C/T)(A/G)TG(A/N), 2, ACACATGG at 798, TCACATGA at 325.
  2. positive strand, negative direction, looking for (T/N)CA(C/T)(A/G)TG(A/N), 2, GCACATGC at 2668, CCATATGT at 42.
  3. positive strand, positive direction, looking for (T/N)CA(C/T)(A/G)TG(A/N), 5, CCACGTGG at 3885, ACACGTGT at 2962, GCACGTGT at 1220, GCATGTGC at 568, GCACGTGT at 548.
  4. negative strand, positive direction, looking for (T/N)CA(C/T)(A/G)TG(A/N), 7, ACATGTGC at 3959, TCACATGT at 3957, CCATGTGA at 3903, GCACATGT at 3743, CCACATGA at 3708, CCACATGG at 2032, ACACGTGC at 571.

Inverse complement is the same as the first four.

MHbox distal promoters

Main article: Distal promoter gene transcriptions
  1. Negative strand, negative direction: TCACATGA at 325.
  1. Negative strand, positive direction: TCACATGT at 3957, CCATGTGA at 3903, CCACATGA at 3708.

MHbox random dataset samplings

  1. MHboxr0: 1, TCATATGG at 2152.
  2. MHboxr1: 3, GCATGTGC at 3892, ACATATGG at 2102, GCATATGC at 1606.
  3. MHboxr2: 3, GCACATGC at 3735, ACATATGA at 1758, CCATGTGA at 167.
  4. MHboxr3: 3, GCACGTGT at 3770, TCATGTGT at 1135, CCATGTGA at 94.
  5. MHboxr4: 5, ACACGTGG at 2288, GCATGTGA at 2244, CCATGTGA at 2225, TCATATGA at 1686, CCACATGC at 910.
  6. MHboxr5: 2, CCATATGA at 1780, ACACGTGA at 60.
  7. MHboxr6: 6, CCACGTGT at 2906, CCACATGA at 2602, GCATGTGA at 2331, TCATGTGA at 1343, GCACGTGC at 655, CCATATGA at 246.
  8. MHboxr7: 1, GCACGTGA at 1857.
  9. MHboxr8: 0.
  10. MHboxr9: 3, ACACATGC at 4072, TCATGTGC at 1976, GCACGTGC at 1188.

RDr arbitrary (evens) (4560-2846) UTRs

  1. MHboxr2: GCACATGC at 3735.

MHboxr alternate (odds) (4560-2846) UTRs

  1. MHboxr1: GCATGTGC at 3892.
  2. MHboxr3: GCACGTGT at 3770.

RDr arbitrary negative direction (evens) (2846-2811) core promoters

RDr alternate negative direction (odds) (2846-2811) core promoters

RDr arbitrary positive direction (odds) (4445-4265) core promoters

RDr alternate positive direction (evens) (4445-4265) core promoters

RDr arbitrary negative direction (evens) (2811-2596) proximal promoters

RDr alternate negative direction (odds) (2811-2596) proximal promoters

RDr arbitrary positive direction (odds) (4265-4050) proximal promoters

RDr alternate positive direction (evens) (4265-4050) proximal promoters

MHboxr arbitrary negative direction (evens) (2596-1) distal promoters

  1. MHboxr0: TCATATGG at 2152.
  2. MHboxr2: ACATATGA at 1758, CCATGTGA at 167.

MHboxr alternate negative direction (odds) (2596-1) distal promoters

  1. MHboxr1: ACATATGG at 2102, GCATATGC at 1606.
  2. MHboxr3: TCATGTGT at 1135, CCATGTGA at 94.

MHboxr arbitrary positive direction (odds) (4050-1) distal promoters

  1. MHboxr1: GCATGTGC at 3892, ACATATGG at 2102, GCATATGC at 1606.
  2. MHboxr3: GCACGTGT at 3770, TCATGTGT at 1135, CCATGTGA at 94.

MHboxr alternate positive direction (evens) (4050-1) distal promoters

  1. MHboxr0: TCATATGG at 2152.
  2. MHboxr2: GCACATGC at 3735, ACATATGA at 1758, CCATGTGA at 167.

MHboxr proximal promoters

Main article: Proximal promoter gene transcriptions
  1. MHboxr6: CCACATGA at 2602.

MHboxr distal promoters

  1. MHboxr0: TCATATGG at 2152.
  2. MHboxr2: ACATATGA at 1758, CCATGTGA at 167.
  3. MHboxr4: GCATGTGA at 2244, CCATGTGA at 2225, TCATATGA at 1686.
  4. MHboxr6: GCATGTGA at 2331, TCATGTGA at 1343, CCATATGA at 246.


  1. MHboxr3: TCATGTGT at 1135, CCATGTGA at 94.
  2. MHboxr5: CCATATGA at 1780, ACACGTGA at 60.
  3. MHboxr7: GCACGTGA at 1857.
  4. MHboxr9: TCATGTGC at 1976.

M-box (Hoek) analysis and results

Main article: Complex locus A1BG and ZNF497 § M-box (Hoek)

Consensus sequences: TCAYRTG or CAYRTGA, TCA(C/T)(A/G)TG or CA(C/T)(A/G)TGA[6] ~ (T/N)CA(C/T)(A/G)TG(A/N).

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 1 10 0.1 0.05
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 1 2 0.5 0.5 ± 0.5 (--1,+-0)
Randoms Distal arbitrary negative 11 10 1.1 0.85 ± 0.25
Randoms Distal alternate negative 6 10 0.6 0.85 ± 0.25
Reals Distal positive 3 2 1.5 1.5 ± 0.5 (-+3,++0)
Randoms Distal arbitrary positive 0 10 0 0
Randoms Distal alternate positive 0 10 0 0

Comparison:

The occurrences of real responsive element consensus sequences are greater than the randoms. This suggests that the real responsive element consensus sequences are likely active or activable.

Using a more general M-box consensus of (T/N)CA(C/T)(A/G)TG(A/N) yielded four sequences in the negative direction and twelve in the positive direction. Of these only TCACATGA at 325 in the negative direction and TCACATGT at 3957, CCATGTGA at 3903, and CCACATGA at 3708 in the positive direction conform to TCAYRTG or CAYRTGA[6]. The random datasets had 25 occurrences of the general consensus but only fifteen fit TCAYRTG or CAYRTGA[6], nine in the arbitrary negative direction and six in the positive direction. The disparity between real occurrences and random occurrences suggests that the real occurrences are likely active or can be activated.

M-box (Ripoll) samplings

Main article: Model samplings

Copying a responsive elements consensus sequence TCACATGA and putting the sequence in "⌘F" finds none between ZNF497 and A1BG or none between ZSCAN22 and A1BG as can be found by the computer programs.

For the Basic programs testing consensus sequence TCACATGA (starting with SuccessablesM-box.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 TCACATGA, 1, TCACATGA at 325.
  2. positive strand, negative direction, looking for TCACATGA, 0.
  3. positive strand, positive direction, looking for TCACATGA, 0.
  4. negative strand, positive direction, looking for TCACATGA, 0.
  5. inverse complement, negative strand, negative direction, looking for TCATGTGA, 0.
  6. inverse complement, positive strand, negative direction, looking for TCATGTGA, 0.
  7. inverse complement, positive strand, positive direction, looking for TCATGTGA, 0.
  8. inverse complement, negative strand, positive direction, looking for TCATGTGA, 0.

M-box distal promoters

Main article: Distal promoter gene transcriptions

Negative strand, negative direction: TCACATGA at 325.

M-box random dataset samplings

  1. M-boxr0: 0.
  2. M-boxr1: 0.
  3. M-boxr2: 0.
  4. M-boxr3: 0.
  5. M-boxr4: 0.
  6. M-boxr5: 0.
  7. M-boxr6: 0.
  8. M-boxr7: 0.
  9. M-boxr8: 0.
  10. M-boxr9: 0.
  11. M-boxr0ci: 0.
  12. M-boxr1ci: 0.
  13. M-boxr2ci: 0.
  14. M-boxr3ci: 0.
  15. M-boxr4ci: 0.
  16. M-boxr5ci: 0.
  17. M-boxr6ci: 0.
  18. M-boxr7ci: 0.
  19. M-boxr8ci: 0.
  20. M-boxr9ci: 0.

M-box (Ripoll) analysis and results

Main article: Complex locus A1BG and ZNF497 § M-box (Ripoll)

The M-box with the consensus sequence TCACATGA[5] occurred only once.

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 0 2 0 0
Randoms Distal arbitrary positive 0 10 0 0
Randoms Distal alternate positive 0 10 0 0

Comparison:

The occurrences of real responsive element consensus sequences are greater than the randoms. This suggests that the real responsive element consensus sequences are likely active or activable.

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. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Corine Bertolotto, Roser Buscà, Patricia Abbe, Karine Bille, Edith Aberdam, Jean-Paul Ortonne, and Robert Ballotti (February 1998). "Different cis-Acting Elements Are Involved in the Regulation of TRP1 and TRP2 Promoter Activities by Cyclic AMP: Pivotal Role of M Boxes (GTCATGTGCT) and of Microphthalmia". Molecular and Cellular Biology. 18 (2): 694–702. PMID 9447965. Retrieved 8 December 2018.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 HGNC (21 December 2019). "DCT dopachrome tautomerase [ Homo sapiens (human) ]". 8600 Rockville Pike, Bethesda MD, 20894 USA: National Center for Biotechnology Information, U.S. National Library of Medicine. Retrieved 29 January 2020.
  3. ↑ RefSeq (March 2009). "TYRP1 tyrosinase related protein 1 [ Homo sapiens (human) ]". 8600 Rockville Pike, Bethesda MD, 20894 USA: National Center for Biotechnology Information, U.S. National Library of Medicine. Retrieved 29 January 2020.
  4. ↑ Yuanyuan Zhao, Jinzhu Meng, Guoqing Cao, Pengfei Gao & Changsheng Dong (28 August 2018). "Screening the optimal activity region of the dopachrome tautomerase gene promoter in sheep skin melanocytes". Journal of Applied Animal Research. 46 (1): 1382–1388. doi:10.1080/09712119.2018.1512497. Retrieved 6 August 2021.
  5. ↑ 5.0 5.1 Vera M. Ripoll, Nicholas A. Meadows, Liza-Jane Raggatt, Ming K. Chang, Allison R. Pettit, Alan I. Cassady and David A. Hume (30 April 2005). "Microphthalmia transcription factor regulates the expression of the novel osteoclast factor GPNMB" (PDF). Gene. 413 (1–2): 32–41. doi:10.1016/j.gene.2008.01.014. Retrieved 18 March 2021.
  6. ↑ 6.0 6.1 6.2 Keith S. Hoek, Natalie C. Schlegel, Ossia M. Eichhoff, Daniel S. Widmer, Christian Praetorius, Steingrimur O. Einarsson, Sigridur Valgeirsdottir, Kristin Bergsteinsdottir, Alexander Schepsky, Reinhard Dummer, Eirikur Steingrimsson (11 November 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research. 21 (6): 665–676. doi:10.1111/j.1755-148X.2008.00505.x. Retrieved 15 December 2022.

External links


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