MTA2

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This article is about proteins. For the Islamic TV channel, see MTA 2.
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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Metastasis-associated protein MTA2 is a protein that in humans is encoded by the MTA2 gene.[1][2]

MTA2 is the second member of the MTA family of genes.[1][3][4] MTA2 protein localizes in the nucleus and is a component of the nucleosome remodeling and the deacetylation complex (NuRD).[4] Similar to the founding family member MTA1, MTA2 functions as a chromatin remodeling factor and regulates gene expression.[5][6] MTA2 is overexpressed in human cancer and its dysregulated level correlates well with cancer invasiveness and aggressive phenotypes.[7]

Discovery

MTA2 was initially recognized as an MTA1 like 1 gene, named MTA1-L1, from a large scale sequencing of randomly selected clones from human cDNA libraries in 1999.[1] Clues about the role of MTA2 in gene expression came from the association of MTA2 polypeptides in the NuRD complex in a proteomic study[3] This was followed by targeted cloning of murine Mta2 in 2001.[8]

Gene and spliced variants

MTA2 is localized on chromosome 11q12-q13.1 in human and on 19B in mice. The 8.6-kb long human MTA2 gene contains 20 exons and seven transcripts inclusive of three protein-coding transcripts but predicted to code for two polypeptides of 688 amino acids and 495 amino acids.[9] The remaining four MTA2 transcripts are non-coding RNA transcripts ranging from 532-bp to 627-bp. The murine Mta2 consists of a 3.1-kb protein-coding transcript to code a protein of 668 amino acids, and five non-coding RNAs transcripts, ranging from 620-bp to 839-bp.

Structure

Amino acid sequence of MTA2 shares 68.2% homology with MTA1’s sequence. MTA2 domains include, a BAH (Bromo-Adjacent Homology), a ELM2 (egl-27 and MTA1 homology), a SANT domain (SWI, ADA2, N-CoR, TFIIIB-B), and a GATA-like zinc finger.[10][11][12] MTA2 is acetylated at lysine 152 within the BAH domain[13]

Function

This gene encodes a protein that has been identified as a component of NuRD, a nucleosome remodeling deacetylase complex identified in the nucleus of human cells. It shows a very broad expression pattern and is strongly expressed in many tissues. It may represent one member of a small gene family that encode different but related proteins involved either directly or indirectly in transcriptional regulation. Their indirect effects on transcriptional regulation may include chromatin remodeling.[2]

MTA2 inhibits estrogen receptor-transactivation functions, and participates in the development of hormones independent of breast cancer cells.[7] The MTA2 participate in the circadian rhythm through CLOCK-BMAL1 complex. MTA2 inhibits the expression of target genes owing to its ability to interact with chromatin remodeling complexes, and modulates pathways involved in cellular functions, including invasion, apoptosis, epithelial-to-mesenchymal transition, and growth of normal and cancer cells[5][7]

Regulation

Expression of MTA2 is stimulated by Sp1 transcription factor [8][14] and repressed by Kaiso.[15] Growth regulatory activity of MTA2 is modulated through its acetylation by histone acetylase p300 [12]. The expression of MTA2 is inhibited by the Rho GDIa in breast cancer cells[16] and by human β-defensins in colon cancer cells.[17] MicroRNAs-146a and miR-34a also regulate the levels of MTA2 mRNA through post-transcriptional mechanism.[18][19][20]

Targets

MTA2 deacetylates the estrogen receptor alpha and p53 and inhibits their transactivation functions.[21][22] MTA2 represses the expression of E-cadherin in non-small-cell lung cancer cells.[23] but stimulates the expression of IL-11 in gastric cancer cells.[24] The MTA2-containing chromatin remodeling complex targets CLOCK-BMAL1 complex.[25]

Interactions

MTA2 has been shown to interact with:

Notes


References

  1. ↑ 1.0 1.1 1.2 Futamura M, Nishimori H, Shiratsuchi T, Saji S, Nakamura Y, Tokino T (1999). "Molecular cloning, mapping, and characterization of a novel human gene, MTA1-L1, showing homology to a metastasis-associated gene, MTA1". Journal of Human Genetics. 44 (1): 52–6. doi:10.1007/s100380050107. PMID 9929979.
  2. ↑ 2.0 2.1 "Entrez Gene: MTA2 metastasis associated 1 family, member 2".
  3. ↑ 3.0 3.1 Zhang Y, Ng HH, Erdjument-Bromage H, Tempst P, Bird A, Reinberg D (Aug 1999). "Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation". Genes & Development. 13 (15): 1924–35. doi:10.1101/gad.13.15.1924. PMC 316920. PMID 10444591.
  4. ↑ 4.0 4.1 Li DQ, Kumar R (2015). "Unravelling the Complexity and Functions of MTA Coregulators in Human Cancer". Advances in Cancer Research. 127: 1–47. doi:10.1016/bs.acr.2015.04.005. PMID 26093897.
  5. ↑ 5.0 5.1 Sen N, Gui B, Kumar R (Dec 2014). "Physiological functions of MTA family of proteins". Cancer Metastasis Reviews. 33 (4): 869–77. doi:10.1007/s10555-014-9514-4. PMC 4245464. PMID 25344801.
  6. ↑ Kumar R (Dec 2014). "Functions and clinical relevance of MTA proteins in human cancer. Preface". Cancer Metastasis Reviews. 33 (4): 835. doi:10.1007/s10555-014-9509-1. PMC 4245326. PMID 25348751.
  7. ↑ 7.0 7.1 7.2 Covington KR, Fuqua SA (Dec 2014). "Role of MTA2 in human cancer". Cancer Metastasis Reviews. 33 (4): 921–8. doi:10.1007/s10555-014-9518-0. PMC 4425804. PMID 25394532.
  8. ↑ 8.0 8.1 Xia L, Zhang Y (May 2001). "Sp1 and ETS family transcription factors regulate the mouse Mta2 gene expression". Gene. 268 (1–2): 77–85. doi:10.1016/s0378-1119(01)00429-2. PMID 11368903.
  9. ↑ Kumar R, Wang RA (May 2016). "Structure, expression and functions of MTA genes". Gene. 582 (2): 112–21. doi:10.1016/j.gene.2016.02.012. PMID 26869315.
  10. ↑ Millard CJ, Watson PJ, Celardo I, Gordiyenko Y, Cowley SM, Robinson CV, Fairall L, Schwabe JW (Jul 2013). "Class I HDACs share a common mechanism of regulation by inositol phosphates". Molecular Cell. 51 (1): 57–67. doi:10.1016/j.molcel.2013.05.020. PMC 3710971. PMID 23791785.
  11. ↑ Alqarni SS, Murthy A, Zhang W, Przewloka MR, Silva AP, Watson AA, Lejon S, Pei XY, Smits AH, Kloet SL, Wang H, Shepherd NE, Stokes PH, Blobel GA, Vermeulen M, Glover DM, Mackay JP, Laue ED (Aug 2014). "Insight into the architecture of the NuRD complex: structure of the RbAp48-MTA1 subcomplex". The Journal of Biological Chemistry. 289 (32): 21844–55. doi:10.1074/jbc.M114.558940. PMC 4139204. PMID 24920672.
  12. ↑ Millard CJ, Fairall L, Schwabe JW (Dec 2014). "Towards an understanding of the structure and function of MTA1". Cancer Metastasis Reviews. 33 (4): 857–67. doi:10.1007/s10555-014-9513-5. PMC 4244562. PMID 25352341.
  13. ↑ Zhou J, Zhan S, Tan W, Cheng R, Gong H, Zhu Q (Feb 2014). "P300 binds to and acetylates MTA2 to promote colorectal cancer cells growth". Biochemical and Biophysical Research Communications. 444 (3): 387–90. doi:10.1016/j.bbrc.2014.01.062. PMID 24468085.
  14. ↑ Zhou C, Ji J, Cai Q, Shi M, Chen X, Yu Y, Liu B, Zhu Z, Zhang J (8 September 2013). "MTA2 promotes gastric cancer cells invasion and is transcriptionally regulated by Sp1". Molecular Cancer. 12 (1): 102. doi:10.1186/1476-4598-12-102. PMC 3851872. PMID 24010737.
  15. ↑ Yoon HG, Chan DW, Reynolds AB, Qin J, Wong J (Sep 2003). "N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso". Molecular Cell. 12 (3): 723–34. doi:10.1016/j.molcel.2003.08.008. PMID 14527417.
  16. ↑ Barone I, Brusco L, Gu G, Selever J, Beyer A, Covington KR, Tsimelzon A, Wang T, Hilsenbeck SG, Chamness GC, Andò S, Fuqua SA (Apr 2011). "Loss of Rho GDIα and resistance to tamoxifen via effects on estrogen receptor α". Journal of the National Cancer Institute. 103 (7): 538–52. doi:10.1093/jnci/djr058. PMC 3071355. PMID 21447808.
  17. ↑ Uraki S, Sugimoto K, Shiraki K, Tameda M, Inagaki Y, Ogura S, Kasai C, Nojiri K, Yoneda M, Yamamoto N, Takei Y, Nobori T, Ito M (Sep 2014). "Human β-defensin-3 inhibits migration of colon cancer cells via downregulation of metastasis-associated 1 family, member 2 expression". International Journal of Oncology. 45 (3): 1059–64. doi:10.3892/ijo.2014.2507. PMID 24969834.
  18. ↑ Li Y, Vandenboom TG, Wang Z, Kong D, Ali S, Philip PA, Sarkar FH (Feb 2010). "miR-146a suppresses invasion of pancreatic cancer cells". Cancer Research. 70 (4): 1486–95. doi:10.1158/0008-5472.CAN-09-2792. PMC 2978025. PMID 20124483.
  19. ↑ Kaller M, Liffers ST, Oeljeklaus S, Kuhlmann K, Röh S, Hoffmann R, Warscheid B, Hermeking H (Aug 2011). "Genome-wide characterization of miR-34a induced changes in protein and mRNA expression by a combined pulsed SILAC and microarray analysis". Molecular & Cellular Proteomics. 10 (8): M111.010462. doi:10.1074/mcp.M111.010462. PMC 3149097. PMID 21566225.
  20. ↑ Zhang Y, Wang XF (Dec 2014). "Post-transcriptional regulation of MTA family by microRNAs in the context of cancer". Cancer Metastasis Reviews. 33 (4): 1011–6. doi:10.1007/s10555-014-9526-0. PMC 4245459. PMID 25332146.
  21. ↑ Cui Y, Niu A, Pestell R, Kumar R, Curran EM, Liu Y, Fuqua SA (Sep 2006). "Metastasis-associated protein 2 is a repressor of estrogen receptor alpha whose overexpression leads to estrogen-independent growth of human breast cancer cells". Molecular Endocrinology. 20 (9): 2020–35. doi:10.1210/me.2005-0063. PMC 4484605. PMID 16645043.
  22. ↑ Luo J, Su F, Chen D, Shiloh A, Gu W (Nov 2000). "Deacetylation of p53 modulates its effect on cell growth and apoptosis". Nature. 408 (6810): 377–81. doi:10.1038/35042612. PMID 11099047.
  23. ↑ Lu X, Kovalev GI, Chang H, Kallin E, Knudsen G, Xia L, Mishra N, Ruiz P, Li E, Su L, Zhang Y (May 2008). "Inactivation of NuRD component Mta2 causes abnormal T cell activation and lupus-like autoimmune disease in mice". The Journal of Biological Chemistry. 283 (20): 13825–33. doi:10.1074/jbc.M801275200. PMC 2376246. PMID 18353770.
  24. ↑ Zhou C, Ji J, Cai Q, Shi M, Chen X, Yu Y, Zhu Z, Zhang J (2 May 2015). "MTA2 enhances colony formation and tumor growth of gastric cancer cells through IL-11". BMC Cancer. 15: 343. doi:10.1186/s12885-015-1366-y. PMC 4419442. PMID 25929737.
  25. ↑ Kim JY, Kwak PB, Weitz CJ (Dec 2014). "Specificity in circadian clock feedback from targeted reconstitution of the NuRD corepressor". Molecular Cell. 56 (6): 738–48. doi:10.1016/j.molcel.2014.10.017. PMID 25453762.
  26. ↑ 26.0 26.1 26.2 26.3 26.4 26.5 Yao YL, Yang WM (Oct 2003). "The metastasis-associated proteins 1 and 2 form distinct protein complexes with histone deacetylase activity". The Journal of Biological Chemistry. 278 (43): 42560–8. doi:10.1074/jbc.M302955200. PMID 12920132.
  27. ↑ You A, Tong JK, Grozinger CM, Schreiber SL (Feb 2001). "CoREST is an integral component of the CoREST- human histone deacetylase complex". Proceedings of the National Academy of Sciences of the United States of America. 98 (4): 1454–8. doi:10.1073/pnas.98.4.1454. PMC 29278. PMID 11171972.
  28. ↑ 28.0 28.1 28.2 28.3 28.4 Zhang Y, Ng HH, Erdjument-Bromage H, Tempst P, Bird A, Reinberg D (Aug 1999). "Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation". Genes & Development. 13 (15): 1924–35. doi:10.1101/gad.13.15.1924. PMC 316920. PMID 10444591.
  29. ↑ 29.0 29.1 Yasui D, Miyano M, Cai S, Varga-Weisz P, Kohwi-Shigematsu T (Oct 2002). "SATB1 targets chromatin remodelling to regulate genes over long distances". Nature. 419 (6907): 641–5. doi:10.1038/nature01084. PMID 12374985.
  30. ↑ Hakimi MA, Dong Y, Lane WS, Speicher DW, Shiekhattar R (Feb 2003). "A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes". The Journal of Biological Chemistry. 278 (9): 7234–9. doi:10.1074/jbc.M208992200. PMID 12493763.
  31. ↑ Sakai H, Urano T, Ookata K, Kim MH, Hirai Y, Saito M, Nojima Y, Ishikawa F (Dec 2002). "MBD3 and HDAC1, two components of the NuRD complex, are localized at Aurora-A-positive centrosomes in M phase". The Journal of Biological Chemistry. 277 (50): 48714–23. doi:10.1074/jbc.M208461200. PMID 12354758.
  32. ↑ Saito M, Ishikawa F (Sep 2002). "The mCpG-binding domain of human MBD3 does not bind to mCpG but interacts with NuRD/Mi2 components HDAC1 and MTA2". The Journal of Biological Chemistry. 277 (38): 35434–9. doi:10.1074/jbc.M203455200. PMID 12124384.

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