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Biology:MTA1

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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 MTA1 is a protein that in humans is encoded by the MTA1 gene. MTA1 is the founding member of the MTA family of genes.[1][2] MTA1 is primarily localized in the nucleus but also found to be distributed in the extra-nuclear compartments.[3] MTA1 is a component of several chromatin remodeling complexes including the nucleosome remodeling and deacetylation complex (NuRD).[4][5] MTA1 regulates gene expression by functioning as a coregulator to integrate DNA-interacting factors to gene activity.[6] MTA1 participates in physiological functions in the normal and cancer cells.[7][8] MTA1 is one of the most upregulated proteins in human cancer and associates with cancer progression, aggressive phenotypes, and poor prognosis of cancer patients.[5][9]

Discovery

MTA1 was first cloned by Toh, Pencil and Nicholson in 1994 as a differentially expressed gene in a highly metastatic rat breast cancer cell line.[1][2] The role in MTA1 in chromatin remodeling was deduced due to the presence of MTA1 polypeptides in the NuRD complex.[4] The first direct target of the MTA1-NuRD complex was ERα.[10] MTA2 was initially recognized as MTA1-like 1 gene, named as MTA1-L1, as a randomly selected clone from a large-scale sequencing effort of human cDNAs by Takashi Tokino's laboratory. MTA2's suspected role in chromatin remodeling was inferred from the prevalence of MTA2 polypeptides with the NuRD complex in a proteomic study(Zhang et al., 1999, Kumar and Wang, 2016).

Gene and spliced variants

The MTA1 is 715/703 amino acids long, coded by one of three genes of the MTA family and localized on chromosome 14q32 in human and on chromosome 12F in mouse. There are 21 exons spread over a region of about 51-kb in human MTA1. Alternative splicing from 21 exons generates 20 transcripts, ranging from 416-bp to 2.9-kb long.[11] However, open-reading frames are present only in eight spliced transcripts which code six proteins and two polypeptides and remaining transcripts are non-coding long RNAs some of which retain intron sequences. Murine Mta1 contains three protein coding transcripts and three non-coding RNA transcripts.[11] Among human MTA1 variants, only two spliced variants are characterized: ZG29p variant is derived from the c-terminal MTA1, with 251 amino acids and 29-kDa molecular weight;[12] and MTA1s variant generated from alternative splicing of a middle exon followed by a frame-shift, is 430 amino acids and 47-kDa molecular weight.[13]

Protein domains

The conserved domains of MTA1 include a BAH (Bromo-Adjacent Homology), an ELM2 (egl-27 and MTA1 homology), a SANT (SWI, ADA2, N-CoR, TFIIIB-B) and a GATA-like zinc finger. The C-terminal divergent region of MTA1 has an Src homology 3-binding domain, acidic regions, and nuclear localization signals. The presence of these domains revealed the role of MTA1 in interactions with modified or unmodified histone and non-histone proteins, chromatin remodeling, and modulation of gene transcription.[5][14][15][16] MTA1 undergoes multiple post-translation modifications: acetylation on lysine 626, ubiquitination on lysine 182 and lysine 626, sumoylation on lysine 509, and methylation on lysine 532.[17][18][19] The structural insights of MTA1 domains are deduced from studies involving complexes with HDAC1 or RbAp48 subunits of the NuRD complexes.[14][15] The MTA1s variant is an N-terminal portion of MTA1 without nuclear localization sequence but contains a novel sequence of 33 amino acids in its C-terminal region. The novel sequence harbors a nuclear receptor binding motif LXXLL which confers MTA1 with an ability to interact with estrogen receptor alpha or other type I nuclear receptors.[13] The ZG29p variant represents the c-terminal MTA1 with two proline-rich SH3 binding sites.[12][20]

Regulation

Expression of MTA1 is influenced by transcription and non-transcriptional mechanisms. MTA1 expression is regulated by growth factors, growth factor receptors, oncogenes, environmental stress, ionizing radiation, inflammation, and hypoxia.[5][8] The transcription of MTA1 is stimulated by transcriptional factors including, c-Myc,[21] SP1,[22] CUTL1 homeodomain,[23] NF-ḵB,[24] HSF1,[25] HIF-1a,[26] and Clock/BMAL1 complex,[27] and inhibited by p53.[28] Non-genomic mechanisms of MTA1 expression include post-transcriptional regulations such as ubiquitination by RING-finger ubiquitin-protein ligase COP1 [29] or interaction with tumor suppressor ARF [24] or micro-RNAs such as miR-30c, miR-661 and miR-125a-3p.[30][31][32][33]

Targets

Functions of MTA1 are regulated by its post-translational modifications, modulating the roles of effector molecules, interacting with other regulatory proteins and chromatin remodeling machinery, and modulating the expression of target genes via interacting with the components of the NuRD complex including HDACs.[5][14][15]

MTA1 suppresses transcription of breast cancer type 1 susceptibility gene,[34] PTEN,[35] p21WAF,[36] guanine nucleotide-binding protein G(i) subunit alpha-2,[17] SMAD family member 7,[37] nuclear receptor subfamily 4 group A member 1,[38] and homeobox protein SIX3,[39] and represses BCL11B[40] as well as E-cadherin expression.[41][42]

MTA1 is a dual coregulatory as it stimulates the transcription of Stat3,[43] breast cancer-amplified sequence 3,[44] FosB,[23] paired box gene 5,[45] transglutaminase 2,[46] myeloid differentiation primary response 88,[47] tumor suppressorp14/p19ARF,[22][48] tyrosine hydroxylase,[49] clock gene CRY1,[27] SUMO2,[18] and Wnt1 and rhodopsin due to release of their transcriptional inhibition by homeodomain protein Six3,[39][50]

MTA1 interacts with ERα and coregulatory factors such as MAT1,[51] MICoA,[52] NRIF3 [55][53] and LMO4， [56],[54] which inhibits ER transactivation activity.[10] MTA1 also deacetylate its target proteins such as p53 and HIF and modulates their transactivation functions.[55][56] Furthermore, MTA1 could potentially modulate the expression of target genes through the microRNA network as MTA1 knockdown results modulation of miR-210, miR-125b, miR-194, miR-103, and miR-500.[57][58]

Cellular functions

MTA1 modulates the expression of target genes due to its ability to act as a corepressor or coactivator. MTA1 targets and/or effector pathways regulate pathways with cellular functions in both normal and cancer cells.[7][8] Physiological functions of MTA1 include: its role in the brain due to MTA1 interactions with DJ1[48] and endophilin-3;[59] regulation of rhodopsin expression in the mouse eye; modifier of circadian rhythm due to MTA1 interactions with the CLOCK-BMAL1 complex and stimulation of Cry-transcription; in heart development due to MTA1-FOG2 interaction; in mammary gland development as MTA1 depletion leads to ductal hypobranching, in spermatogenesis; in immunomodulation due to differential effects on the expression of cytokines in the resting and activated macrophage; in liver regeneration following hepatic injury; differentiation of mesenchymal stem cells into osteogenic axis; and a component of DNA-damage response.[7] In cancer cells, MTA1 and its downstream effectors regulate genes and/or pathways with roles in transformation, invasion, survival, angiogenesis, epithelial-to-mesenchymal transition, metastasis, DNA damage response, and hormone-independence of breast cancer.[5][8]

Notes


References

  1. ↑ 1.0 1.1 "A novel candidate metastasis-associated gene, mta1, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analyses". The Journal of Biological Chemistry 269 (37): 22958–63. Sep 1994. doi:10.1016/S0021-9258(17)31603-4. PMID 8083195. 
  2. ↑ 2.0 2.1 "Properties and clinical relevance of MTA1 protein in human cancer". Cancer and Metastasis Reviews 33 (4): 891–900. Dec 2014. doi:10.1007/s10555-014-9516-2. PMID 25359582. 
  3. ↑ "Subcellular localization of MTA proteins in normal and cancer cells". Cancer and Metastasis Reviews 33 (4): 843–56. Dec 2014. doi:10.1007/s10555-014-9511-7. PMID 25398252. 
  4. ↑ 4.0 4.1 "NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities". Molecular Cell 2 (6): 851–61. Dec 1998. doi:10.1016/s1097-2765(00)80299-3. PMID 9885572. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Advances in Cancer Research. 127. 2015. pp. 1–47. doi:10.1016/bs.acr.2015.04.005. ISBN 9780128029206. 
  6. ↑ Kumar, Rakesh; Gururaj, Anupama E. (2008). "Coregulators as Oncogenes and Tumor Suppressors". Nuclear Receptor Coregulators and Human Diseases. Hackensack, N.J.: World Scientific. pp. 195–218. doi:10.1142/9789812819178_0004. ISBN 978-981-281-917-8. 
  7. ↑ 7.0 7.1 7.2 "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. 
  8. ↑ 8.0 8.1 8.2 8.3 "Role of MTA1 in cancer progression and metastasis". Cancer and Metastasis Reviews 33 (4): 879–89. Dec 2014. doi:10.1007/s10555-014-9515-3. PMID 25344802. 
  9. ↑ "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. 
  10. ↑ 10.0 10.1 "Transcriptional repression of oestrogen receptor by metastasis-associated protein 1 corepressor". Nature Cell Biology 3 (1): 30–7. Jan 2001. doi:10.1038/35050532. PMID 11146623. 
  11. ↑ 11.0 11.1 "Structure, expression and functions of MTA genes". Gene 582 (2): 112–21. May 2016. doi:10.1016/j.gene.2016.02.012. PMID 26869315. 
  12. ↑ 12.0 12.1 "A novel zymogen granule protein (ZG29p) and the nuclear protein MTA1p are differentially expressed by alternative transcription initiation in pancreatic acinar cells of the rat". Journal of Cell Science 112 (15): 2539–48. Aug 1999. doi:10.1242/jcs.112.15.2539. PMID 10393810. 
  13. ↑ 13.0 13.1 "A naturally occurring MTA1 variant sequesters oestrogen receptor-alpha in the cytoplasm". Nature 418 (6898): 654–7. Aug 2002. doi:10.1038/nature00889. PMID 12167865. Bibcode: 2002Natur.418..654K. 
  14. ↑ 14.0 14.1 14.2 "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. 
  15. ↑ 15.0 15.1 15.2 "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. 
  16. ↑ "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. 
  17. ↑ 17.0 17.1 "Acetylation-dependent oncogenic activity of metastasis-associated protein 1 co-regulator". EMBO Reports 11 (9): 691–7. Sep 2010. doi:10.1038/embor.2010.99. PMID 20651739. 
  18. ↑ 18.0 18.1 "SUMOylation and SUMO-interacting motif (SIM) of metastasis tumor antigen 1 (MTA1) synergistically regulate its transcriptional repressor function". The Journal of Biological Chemistry 286 (51): 43793–808. Dec 2011. doi:10.1074/jbc.M111.267237. PMID 21965678. 
  19. ↑ "A core chromatin remodeling factor instructs global chromatin signaling through multivalent reading of nucleosome codes". Molecular Cell 49 (4): 704–18. Feb 2013. doi:10.1016/j.molcel.2012.12.016. PMID 23352453. 
  20. ↑ "SH3 binding sites of ZG29p mediate an interaction with amylase and are involved in condensation-sorting in the exocrine rat pancreas". Biochemistry 39 (32): 9893–900. Aug 2000. doi:10.1021/bi000876i. PMID 10933808. 
  21. ↑ "Metastasis-associated protein 1 (MTA1) is an essential downstream effector of the c-MYC oncoprotein". Proceedings of the National Academy of Sciences of the United States of America 102 (39): 13968–73. Sep 2005. doi:10.1073/pnas.0502330102. PMID 16172399. Bibcode: 2005PNAS..10213968Z. 
  22. ↑ 22.0 22.1 "Bidirectional autoregulatory mechanism of metastasis-associated protein 1-alternative reading frame pathway in oncogenesis". Proceedings of the National Academy of Sciences of the United States of America 108 (21): 8791–6. May 2011. doi:10.1073/pnas.1018389108. PMID 21555589. Bibcode: 2011PNAS..108.8791L. 
  23. ↑ 23.0 23.1 "TGF-β1 signaling targets metastasis-associated protein 1, a new effector in epithelial cells". Oncogene 30 (19): 2230–41. May 2011. doi:10.1038/onc.2010.608. PMID 21258411. 
  24. ↑ "Metastasis-associated protein 1/nucleosome remodeling and histone deacetylase complex in cancer". Cancer Research 72 (2): 387–94. Jan 2012. doi:10.1158/0008-5472.CAN-11-2345. PMID 22253283. 
  25. ↑ "Heat shock factor 1 represses estrogen-dependent transcription through association with MTA1". Oncogene 27 (13): 1886–93. Mar 2008. doi:10.1038/sj.onc.1210834. PMID 17922035. 
  26. ↑ "Metastasis-associated protein 1 enhances stability of hypoxia-inducible factor-1alpha protein by recruiting histone deacetylase 1". The EMBO Journal 25 (6): 1231–41. Mar 2006. doi:10.1038/sj.emboj.7601025. PMID 16511565. 
  27. ↑ 27.0 27.1 "Metastasis-associated protein 1 is an integral component of the circadian molecular machinery". Nature Communications 4: 2545. 2013. doi:10.1038/ncomms3545. PMID 24089055. Bibcode: 2013NatCo...4.2545L. 
  28. ↑ "MTA1 coregulator regulates p53 stability and function". The Journal of Biological Chemistry 284 (50): 34545–52. Dec 2009. doi:10.1074/jbc.M109.056499. PMID 19837670. 
  29. ↑ "E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1". Proceedings of the National Academy of Sciences of the United States of America 106 (41): 17493–8. Oct 2009. doi:10.1073/pnas.0908027106. PMID 19805145. Bibcode: 2009PNAS..10617493L. 
  30. ↑ "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. 
  31. ↑ "Estrogen regulates the tumour suppressor MiRNA-30c and its target gene, MTA-1, in endometrial cancer". PLOS ONE 9 (3): e90810. 2014. doi:10.1371/journal.pone.0090810. PMID 24595016. Bibcode: 2014PLoSO...990810K. 
  32. ↑ "MicroRNA-661, a c/EBPalpha target, inhibits metastatic tumor antigen 1 and regulates its functions". Cancer Research 69 (14): 5639–42. Jul 2009. doi:10.1158/0008-5472.CAN-09-0898. PMID 19584269. 
  33. ↑ "miR-125a-3p targets MTA1 to suppress NSCLC cell proliferation, migration, and invasion". Acta Biochimica et Biophysica Sinica 47 (7): 496–503. Jul 2015. doi:10.1093/abbs/gmv039. PMID 25998575. 
  34. ↑ "MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene". Oncogene 27 (14): 1971–80. Mar 2008. doi:10.1038/sj.onc.1210839. PMID 17922032. 
  35. ↑ "Metastasis-associated protein 1/histone deacetylase 4-nucleosome remodeling and deacetylase complex regulates phosphatase and tensin homolog gene expression and function". The Journal of Biological Chemistry 287 (33): 27843–50. Aug 2012. doi:10.1074/jbc.M112.348474. PMID 22700976. 
  36. ↑ "Revelation of p53-independent function of MTA1 in DNA damage response via modulation of the p21 WAF1-proliferating cell nuclear antigen pathway". The Journal of Biological Chemistry 285 (13): 10044–52. Mar 2010. doi:10.1074/jbc.M109.079095. PMID 20071335. 
  37. ↑ "MTA1-mediated transcriptional repression of SMAD7 in breast cancer cell lines". European Journal of Cancer 49 (2): 492–9. Jan 2013. doi:10.1016/j.ejca.2012.06.019. PMID 22841502. 
  38. ↑ "Repression of NR4A1 by a chromatin modifier promotes docetaxel resistance in PC-3 human prostate cancer cells". FEBS Letters 587 (16): 2542–51. Aug 2013. doi:10.1016/j.febslet.2013.06.029. PMID 23831020. 
  39. ↑ 39.0 39.1 "Metastasis-associated protein 1 and its short form variant stimulates Wnt1 transcription through promoting its derepression from Six3 corepressor". Cancer Research 70 (16): 6649–58. Aug 2010. doi:10.1158/0008-5472.CAN-10-0909. PMID 20682799. 
  40. ↑ "BCL11B functionally associates with the NuRD complex in T lymphocytes to repress targeted promoter". Oncogene 24 (45): 6753–64. Oct 2005. doi:10.1038/sj.onc.1208904. PMID 16091750. 
  41. ↑ "Metastasis-associated protein 1 promotes tumor invasion by downregulation of E-cadherin". International Journal of Oncology 44 (3): 812–8. Mar 2014. doi:10.3892/ijo.2014.2253. PMID 24424621. 
  42. ↑ "The metastasis-associated gene MTA1 is upregulated in advanced ovarian cancer, represses ERbeta, and enhances expression of oncogenic cytokine GRO". Cancer Biology & Therapy 7 (9): 1460–7. Sep 2008. doi:10.4161/cbt.7.9.6427. PMID 18719363. 
  43. ↑ "MTA1 promotes STAT3 transcription and pulmonary metastasis in breast cancer". Cancer Research 73 (12): 3761–70. Jun 2013. doi:10.1158/0008-5472.CAN-12-3998. PMID 23580571. 
  44. ↑ "MTA1, a transcriptional activator of breast cancer amplified sequence 3". Proceedings of the National Academy of Sciences of the United States of America 103 (17): 6670–5. Apr 2006. doi:10.1073/pnas.0601989103. PMID 16617102. Bibcode: 2006PNAS..103.6670G. 
  45. ↑ "Identification of Pax5 as a target of MTA1 in B-cell lymphomas". Cancer Research 67 (15): 7132–8. Aug 2007. doi:10.1158/0008-5472.CAN-07-0750. PMID 17671180. 
  46. ↑ "MTA1 coregulation of transglutaminase 2 expression and function during inflammatory response". The Journal of Biological Chemistry 286 (9): 7132–8. Mar 2011. doi:10.1074/jbc.M110.199273. PMID 21156794. 
  47. ↑ "MTA1 coregulator regulates LPS response via MyD88-dependent signaling". The Journal of Biological Chemistry 285 (43): 32787–92. Oct 2010. doi:10.1074/jbc.M110.151340. PMID 20702415. 
  48. ↑ 48.0 48.1 "Mi-2/NuRD complex making inroads into DNA-damage response pathway". Cell Cycle 9 (11): 2071–9. Jun 2010. doi:10.4161/cc.9.11.11735. PMID 20505336. 
  49. ↑ "Multiple coregulatory control of tyrosine hydroxylase gene transcription". Proceedings of the National Academy of Sciences of the United States of America 108 (10): 4200–5. Mar 2011. doi:10.1073/pnas.1101193108. PMID 21368136. Bibcode: 2011PNAS..108.4200R. 
  50. ↑ "Repression of Six3 by a corepressor regulates rhodopsin expression". Proceedings of the National Academy of Sciences of the United States of America 104 (32): 13128–33. Aug 2007. doi:10.1073/pnas.0705878104. PMID 17666527. Bibcode: 2007PNAS..10413128M. 
  51. ↑ "MTA1 interacts with MAT1, a cyclin-dependent kinase-activating kinase complex ring finger factor, and regulates estrogen receptor transactivation functions". The Journal of Biological Chemistry 278 (13): 11676–85. Mar 2003. doi:10.1074/jbc.M209570200. PMID 12527756. 
  52. ↑ "MICoA, a novel metastasis-associated protein 1 (MTA1) interacting protein coactivator, regulates estrogen receptor-alpha transactivation functions". The Journal of Biological Chemistry 278 (21): 19209–19. May 2003. doi:10.1074/jbc.M301968200. PMID 12639951. 
  53. ↑ "Metastasis-associated protein 1 interacts with NRIF3, an estrogen-inducible nuclear receptor coregulator". Molecular and Cellular Biology 24 (15): 6581–91. Aug 2004. doi:10.1128/MCB.24.15.6581-6591.2004. PMID 15254226. 
  54. ↑ "Negative regulation of estrogen receptor alpha transactivation functions by LIM domain only 4 protein". Cancer Research 65 (22): 10594–601. Nov 2005. doi:10.1158/0008-5472.CAN-05-2268. PMID 16288053. 
  55. ↑ "Metastasis-associated protein 1 inhibits p53-induced apoptosis". Oncology Reports 18 (5): 1311–4. Nov 2007. doi:10.3892/or.18.5.1311. PMID 17914590. 
  56. ↑ "Metastasis-associated protein 1 enhances angiogenesis by stabilization of HIF-1alpha". Oncology Reports 16 (4): 929–35. Oct 2006. doi:10.3892/or.16.4.929. PMID 16969516. 
  57. ↑ "MTA1 gene silencing inhibits invasion and alters the microRNA expression profile of human lung cancer cells". Oncology Reports 28 (1): 218–24. Jul 2012. doi:10.3892/or.2012.1770. PMID 22576802. 
  58. ↑ "MTA1 promotes the invasion and migration of non-small cell lung cancer cells by downregulating miR-125b". Journal of Experimental & Clinical Cancer Research 32 (1): 33. 29 May 2013. doi:10.1186/1756-9966-32-33. PMID 23718732. 
  59. ↑ "Direct interaction between metastasis-associated protein 1 and endophilin 3". FEBS Letters 579 (17): 3731–6. Jul 2005. doi:10.1016/j.febslet.2005.05.069. PMID 15978591. 

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