Biology:MTA2

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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), an 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 "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. 1999. doi:10.1007/s100380050107. PMID 9929979. 
  2. ↑ 2.0 2.1 "Entrez Gene: MTA2 metastasis associated 1 family, member 2". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9219. 
  3. ↑ 3.0 3.1 "Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation". Genes & Development 13 (15): 1924–35. Aug 1999. doi:10.1101/gad.13.15.1924. PMID 10444591. 
  4. ↑ 4.0 4.1 Unravelling the Complexity and Functions of MTA Coregulators in Human Cancer. 127. 2015. 1–47. doi:10.1016/bs.acr.2015.04.005. ISBN 9780128029206. 
  5. ↑ 5.0 5.1 "Physiological functions of MTA family of proteins". Cancer and Metastasis Reviews 33 (4): 869–77. Dec 2014. doi:10.1007/s10555-014-9514-4. PMID 25344801. 
  6. ↑ "Functions and clinical relevance of MTA proteins in human cancer. Preface". Cancer and Metastasis Reviews 33 (4): 835. Dec 2014. doi:10.1007/s10555-014-9509-1. PMID 25348751. 
  7. ↑ 7.0 7.1 7.2 "Role of MTA2 in human cancer". Cancer and Metastasis Reviews 33 (4): 921–8. Dec 2014. doi:10.1007/s10555-014-9518-0. PMID 25394532. 
  8. ↑ 8.0 8.1 "Sp1 and ETS family transcription factors regulate the mouse Mta2 gene expression". Gene 268 (1–2): 77–85. May 2001. doi:10.1016/s0378-1119(01)00429-2. PMID 11368903. 
  9. ↑ "Structure, expression and functions of MTA genes". Gene 582 (2): 112–21. May 2016. doi:10.1016/j.gene.2016.02.012. PMID 26869315. 
  10. ↑ "Class I HDACs share a common mechanism of regulation by inositol phosphates". Molecular Cell 51 (1): 57–67. Jul 2013. doi:10.1016/j.molcel.2013.05.020. PMID 23791785. 
  11. ↑ "Insight into the architecture of the NuRD complex: structure of the RbAp48-MTA1 subcomplex". The Journal of Biological Chemistry 289 (32): 21844–55. Aug 2014. doi:10.1074/jbc.M114.558940. PMID 24920672. 
  12. ↑ "Towards an understanding of the structure and function of MTA1". Cancer and Metastasis Reviews 33 (4): 857–67. Dec 2014. doi:10.1007/s10555-014-9513-5. PMID 25352341. 
  13. ↑ "P300 binds to and acetylates MTA2 to promote colorectal cancer cells growth". Biochemical and Biophysical Research Communications 444 (3): 387–90. Feb 2014. doi:10.1016/j.bbrc.2014.01.062. PMID 24468085. 
  14. ↑ "MTA2 promotes gastric cancer cells invasion and is transcriptionally regulated by Sp1". Molecular Cancer 12 (1): 102. 8 September 2013. doi:10.1186/1476-4598-12-102. PMID 24010737. 
  15. ↑ "N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso". Molecular Cell 12 (3): 723–34. Sep 2003. doi:10.1016/j.molcel.2003.08.008. PMID 14527417. 
  16. ↑ "Loss of Rho GDIα and resistance to tamoxifen via effects on estrogen receptor α". Journal of the National Cancer Institute 103 (7): 538–52. Apr 2011. doi:10.1093/jnci/djr058. PMID 21447808. 
  17. ↑ "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. Sep 2014. doi:10.3892/ijo.2014.2507. PMID 24969834. 
  18. ↑ "miR-146a suppresses invasion of pancreatic cancer cells". Cancer Research 70 (4): 1486–95. Feb 2010. doi:10.1158/0008-5472.CAN-09-2792. PMID 20124483. 
  19. ↑ "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. Aug 2011. doi:10.1074/mcp.M111.010462. PMID 21566225. 
  20. ↑ "Post-transcriptional regulation of MTA family by microRNAs in the context of cancer". Cancer and Metastasis Reviews 33 (4): 1011–6. Dec 2014. doi:10.1007/s10555-014-9526-0. PMID 25332146. 
  21. ↑ "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. Sep 2006. doi:10.1210/me.2005-0063. PMID 16645043. 
  22. ↑ "Deacetylation of p53 modulates its effect on cell growth and apoptosis". Nature 408 (6810): 377–81. Nov 2000. doi:10.1038/35042612. PMID 11099047. Bibcode: 2000Natur.408..377L. 
  23. ↑ "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. May 2008. doi:10.1074/jbc.M801275200. PMID 18353770. 
  24. ↑ "MTA2 enhances colony formation and tumor growth of gastric cancer cells through IL-11". BMC Cancer 15: 343. 2 May 2015. doi:10.1186/s12885-015-1366-y. PMID 25929737. 
  25. ↑ "Specificity in circadian clock feedback from targeted reconstitution of the NuRD corepressor". Molecular Cell 56 (6): 738–48. Dec 2014. doi:10.1016/j.molcel.2014.10.017. PMID 25453762. 
  26. ↑ 26.0 26.1 26.2 26.3 26.4 26.5 "The metastasis-associated proteins 1 and 2 form distinct protein complexes with histone deacetylase activity". The Journal of Biological Chemistry 278 (43): 42560–8. Oct 2003. doi:10.1074/jbc.M302955200. PMID 12920132. 
  27. ↑ "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. Feb 2001. doi:10.1073/pnas.98.4.1454. PMID 11171972. Bibcode: 2001PNAS...98.1454Y. 
  28. ↑ 28.0 28.1 28.2 28.3 28.4 "Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation". Genes & Development 13 (15): 1924–35. Aug 1999. doi:10.1101/gad.13.15.1924. PMID 10444591. 
  29. ↑ 29.0 29.1 "SATB1 targets chromatin remodelling to regulate genes over long distances". Nature 419 (6907): 641–5. Oct 2002. doi:10.1038/nature01084. PMID 12374985. Bibcode: 2002Natur.419..641Y. https://digital.library.unt.edu/ark:/67531/metadc733622/. 
  30. ↑ "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. Feb 2003. doi:10.1074/jbc.M208992200. PMID 12493763. 
  31. ↑ "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. Dec 2002. doi:10.1074/jbc.M208461200. PMID 12354758. 
  32. ↑ "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. Sep 2002. doi:10.1074/jbc.M203455200. PMID 12124384. 

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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