Metastasis-associated protein MTA2 is a protein that in humans is encoded by the MTA2gene.[5][6]
MTA2 is the second member of the MTA family of genes.[5][7][8] MTA2 protein localizes in the nucleus and is a component of the nucleosome remodeling and the deacetylation complex (NuRD).[8] Similar to the founding family member MTA1, MTA2 functions as a chromatin remodeling factor and regulates gene expression.[9][10] MTA2 is overexpressed in human cancer and its dysregulated level correlates well with cancer invasiveness and aggressive phenotypes.[11]
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.[5] Clues about the role of MTA2 in gene expression came from the association of MTA2 polypeptides in the NuRD complex in a proteomic study[7] This was followed by targeted cloning of murine Mta2 in 2001.[12]
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.[13] 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.[14][15][16] MTA2 is acetylated at lysine 152 within the BAH domain[17]
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.[6]
MTA2 inhibits estrogen receptor-transactivation functions, and participates in the development of hormones independent of breast cancer cells.[11] 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[9][11]
Regulation
Expression of MTA2 is stimulated by Sp1 transcription factor[12][18] and repressed by Kaiso.[19] 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[20] and by human β-defensins in colon cancer cells.[21] MicroRNAs-146a and miR-34a also regulate the levels of MTA2 mRNA through post-transcriptional mechanism.[22][23][24]
Targets
MTA2 deacetylates the estrogen receptor alpha and p53 and inhibits their transactivation functions.[25][26] MTA2 represses the expression of E-cadherin in non-small-cell lung cancer cells.[27] but stimulates the expression of IL-11 in gastric cancer cells.[28] The MTA2-containing chromatin remodeling complex targets CLOCK-BMAL1 complex.[29]
^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. PMID24468085.
