Emerging roles of MTA family members in human cancers

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Abstract

Metastasis-associated genes (MTAs) represent a rapidly growing novel gene family. At present, there are three different known genes (MTA1, MTA2, and MTA3) and six reported isoforms (MTA1, MTA1s, MTA1-ZG29p, MTA2, MTA3, MTA3L). MTA1, MTA2, and MTA3 are components of the nucleosome remodeling and deacetylation complex, which is associated with adenosine triphosphate-dependent chromatin remodeling and transcriptional regulation. MTA proteins, as a part of the NuRD complex (nuclear remodeling and deacetylation complex), are thought to modulate transcription by influencing the status of chromatin remodeling. MTA1 overexpression is closely correlated with an aggressive course in several human carcinomas. Recent studies have shown that growth factor stimulation of breast cancer cells induces the expression of MTA1 and its interaction with and repression of the estrogen receptor (ER) transactivation function, leading to enhanced anchorage-independent growth in vitro and hormone independence. Furthermore, the status of the ER pathway modulates the expression of MTA3 as well as epithelial-to-mesenchymal transition in human breast tumors. MTA1 expression is not restricted to tumors; however, several normal mouse tissues and organs also express substantial levels of MTA1. Thus, MTA1 may play a role in both the physiologic and the pathologic states of cells. In Caenorhabditis elegans, MTA1-like genes regulate cell polarity, migration, embryonic patterning, and vulva development. In addition, two naturally occurring variants of MTA1, MTA1-ZG29p, and MTA1s have also been identified. ZG29p is an N-terminal truncated form of MTA1 and is present in the zymogen granules of the pancreas. In contrast, MTA1s is the C-terminal truncated form present in the cytoplasm. MTA1s binds and inhibits the nuclear functions of the ER by sequestering it to cytoplasm, stimulating the mitogen-activated protein kinase pathway. Furthermore, breast tumors with no or low ER in the nucleus exhibit elevated levels of MTA1s and cytoplasmic subcellular localization of the ER. This article reviews the current status of MTA biochemistry and its implications for tumor biology.

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.).

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