MTA1 of the MTA (metastasis-associated) gene family and its encoded proteins: molecular and regulatory functions and role in human cancer progression

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MTA1 (a metastasis-associated gene) is a newly discovere d human gene (residing on chromsome 14q32.3) that belongs to a family of cancer progression-related genes ( MTA ). The mRNA product of MTA1 along with its protein product MTA1 have been reported to be over-expressed in a wide variety of animal and human tumors. For example, the expression of MTA1 and its encoded protein MTA1 correlates with the malignant properties of many human cancers, including cancers of the breast, colon, stomach, li ver, prostate and others. The MTA proteins have bee n shown to be ubiquitinated transcriptional co-repressors that fu nction in histone deacetylation and are part of the NuRD complex, a nucleosome remodeling and histone deacetylating complex whose stability appears to be regulated by ubi quitinated MTA1 binding to E3 ubiquitin ligase constitutive ph otomorphogenesis protein-1 (COP1). The MTA1 protein plays an essential role in c-MYC-mediated cell transformatio n, and its expression correlates with mammary gland tumor formation. In the latter, MTA1 helps convert mammary cells to more aggressive phenotypes by repression of the estrogen receptor (ER) via trans-activation through deacetylation of chromatin in the ER-responsive el ement of ERresponsive genes. Another member of the MTA family, MTA3, is induced by estrogen and represses the exp ression of the transcriptional repressor Snail, a master regul ator of epithelial to mesenchymal transformation, r esulting in the expression of the cell adhesion molecule E-cadherin and maintenance of a differentiated, normal epithel ial phenotype in mammary cells. An important activity mediated by both MTA1 and MTA2 is deacylation and inactivation of tumor suppressor p53protein, in part by controlling its s tability by inhibiting ubiquitination, leading to i nhibition of growth arrest and apoptosis. Another factor deacetylated a nd stabilized by MTA1 NuRD complex is hypoxia-inducible factor1α (HIF-1α), which is involved in angiogenesis. Therefore, th e MTA proteins represent a possible set of master c oregulatory molecules involved in the carcinogenesis and progression of various malignant tumors. As su ch, they could be important new tools for cancer diagnosis and tre atment.