Emerging roles of MTA family members in human cancers☆
Section snippets
Sequence, structure, and functional domains of MTA1, 2, and 3
The nucleotide sequences of MTA1, 2, and 3 cDNAs share about 30% homology with each other. However, at the protein level, the homology among the amino acids of MTA1, 2, and 3 is about 60% (Fig 1). The MTA1 gene is localized on chromosome 14q32.3 in humans and on chromosome 12F in mice.7 The MTA2 gene is localized in mouse chromosome19B, while chromosome localization of MTA3 remains unidentified. In Drosophila, there is only one MTA-like protein, with around 50% similarity in its amino acid
Regulation of MTA genes
MTA1 and MTA2 are expressed in most normal tissues, though in different levels. For example, testis, brain, and liver express relatively higher levels, while skeletal muscles express the lowest level. The expression pattern of MTA3 is generally similar to that of MTA1 but is highest in the liver.1, 9, 10 Very little published data are available about the regulation of MTA genes, but these data suggest that heregulin, a natural ligand for human epidermal growth factor receptor-3 and -4 (HER3 and
MTA proteins pattern the embryonic development of C. elegans
Because all three members of MTA are components of the NuRD complex, their molecules are thought to participate in the regulation of embryonic development. So far, MTA gene mutations have been studied only in C. elegans. A total of 1,090 somatic cells are present in C. elegans during its entire process of development. Because the fate and differentiation of each cell is clearly known, C. elegans provides an excellent model for developmental studies. Two human MTA counterpart genes have been
MTA and cancer
Mortality from breast cancer and other solid malignancies results almost entirely from the invasion and metastasis of neoplastic cells of primary tumors to distant organ sites. Therefore, identifying the genes involved in the metastasis cascade is an important research goal. Toh et al1 used differential cDNA library screening to identify the genes relevant to the metastatic phenotype. They were the first to describe the MTA1 gene, whose expression they correlated with the metastatic potential
MTA1 regulation of estrogen receptor transactivation
Though accumulating data indicate that MTA1 expression is associated with metastasis in a variety of tumors, the nature of its targets remains largely unknown. Given the fact that it regulates cell polarity and cell migration in the lower animal C. elegans, the same kind of mechanism may also be true in mammals. Recent studies have shown that heregulin, a natural ligand for HER3 and HER4, promotes the development of a hormone-independent phenotype and represses the transactivation functions of
MTA1 gene derivative-zymogen granule protein ZG29p
The gene encoding the ZG29p protein was cloned from a rat pancreas cDNA library by immunoscreening with a polyclonal antibody against pancreatic zymogen granules. Sequence analysis showed that the MTA1 gene coded this protein, but that transcription started at a different site from that of MTA1.11 From published data and genome database data (accession no. AF450245), it appears that ZG29p is coded by the last seven exons of MTA1. The thirteenth intron that precedes the start site of ZG29p
MTA1 gene derivative-MTA1s
A second naturally occurring variant of MTA1 was recently discovered.23, 24 This variant, named MTA1s (for short version of MTA1), is a N-terminal truncated form of MTA1, generated by alternative splicing at a cryptic splice site in exon 14 and deletion of 47 base-pair nucleotides (Fig 4). This discovery led to identification of 33 novel amino acids with no obvious similarity to the proteins included in the genome database except for a very conserved LXILL motif known for nuclear receptor
Conclusion
MTA1 was identified through its association with cancer metastasis, but the mechanism by which it promotes cancer progression was unknown until recently. It is increasingly clear that MTA proteins are a large family encoded by the same or different genes. Several MTA proteins are components of the NuRD complex and may involve histone deacetylase and perhaps other co-regulators in modifying chromatin. Alternatively, a short version of MTA1 also sequesters ER in the cytoplasm and redirects the ER
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Supported by National Institute of Health grant nos. CA80066 and CA84456 and Susan Komen Foundation grant BT200083 (R.K.).