Metastasis Tumor Antigens, an Emerging Family of Multifaceted Master Coregulators

Abstract

Regulation of fundamental genetic processes demands dynamic participation of transcription factors, their coregulators, and multiprotein chromatin remodeling activities at target genes. One family of chromatin modifiers that is ubiquitously expressed is the metastasis tumor antigens (MTA), which are integral parts of nucleosome remodeling and histone deacetylation (NuRD) complexes. MTA family members exist in distinct NuRD complexes, and functional redundancy is lacking among MTA family members. MTA proteins regulate divergent cellular pathways, including hormonal action, epithelial-to-mesenchymal transitions, differentiation, protein stability and development, and cell fate programs by modifying the acetylation status of crucial target genes. Intriguingly, at least one member of this family, MTA1, itself undergoes acetylation and acts as a coactivator in certain contexts. We discuss the roles of the MTA family of chromatin modifiers, with an emphasis on their physiologic functions.Dynamic alterations in chromatin structure facilitate or repress access of transcription complexes to target DNAs, leading to transcriptional changes and the regulation of functions associated with the gene products (1). These complexes modify DNA accessibility for cofactors by affecting DNA-histone interactions, nucleosome sliding, or relocation. In addition, the transcriptional state is influenced by covalent modification of the core histones (2). Among histone modifications, acetylation plays a pivotal role in chromatin remodeling (3). Core histones are subject to reversible acetylation at select lysine residues in their N-terminal domains through the coordinate activity of histone acetyltransferases and histone deacetylases (HDACs) 2 (3). Histone acetylation correlates with transcriptional activity, whereas deacetylation favors transcriptional repression. The mechanism of action of histone acetyltransferases is extensively reviewed elsewhere in the literature (4). Here we discuss the current understanding of the MTA family of coregulators, which are essential components of HDAC-containing NuRD transcriptional complexes. NuRD Complex, a Dynamic Switch for Histone Deacetylation and Chromatin RemodelingDeacetylation of histones via HDACs is carried out by two major complexes, Sin3 and NuRD (5, 6). The Sin3 complex contains seven polypeptides: HDAC1, HDAC2, RbAp46, RbAp48, Sin3, SAP18, and SAP30. This complex participates in nuclear hormone receptor repression of target genes (5, 7). NuRD complexes share four core proteins (HDAC1, HDAC2, RbAp46, and RbAp48) with the Sin3 complex and contain Mi-2␣/␤, MTA1/2, and p66 (5). In the NuRD complex, HDAC1/2 participate in the deacetylation process; Mi-2␣/␤ proteins with a chromodomain exhibit a DNA helicase/ATPase activity; and RbAp46/48 participate in histone binding. The roles of p66␣/␤ in NuRD complex are complex as p66 proteins are sumoylated, and SUMO-modified p66␣ efficiently interacts with HDAC1, whereas RbAp46 binds to SUMO-modified p66␤ (8, 9). All three MTA family proteins are found ...

Metastasis tumor antigen 1 is involved in the resistance to heat stress‐induced testicular apoptosis

“…To date, knowledge of upstream regulators of the MTAs is limited [20]. To this end, compelling evidence indicates that a plethora of heterologous endocrine signals modulate the expression of MTA1 in vitro.…”

Coordinate activation of inflammatory gene networks, alveolar destruction and neonatal death in AKNA deficient mice

“…Multicellular development, maturation and function require the timely activation or inhibition of a myriad of genes controlled by central regulatory mechanisms [1,2]. Although homeobox proteins have been established as master gene transcription factors [46], DNA architecturemodulating AT-hook proteins constitute an evolutionarily conserved family with analogous global gene-regulation functions [1,2,4,6,9].…”

“…Cell responses to extracellular cues depend on coordinated and timely regulation of pathway-specific gene networks, whose expression is controlled by master regulators [1][2][3]. Examples of such regulators include AThook proteins, a family of transcription factors that target genes with A/T-rich promoters [4][5][6] and orchestrate their activation or repression [7][8][9][10][11].…”

The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis

“…Each MTA member modifies the functional specificities of the Mi2/NuRD complexes relevant to its upstream and downstream signaling pathways and molecular targets. Specifically, MTA1 is expressed at high levels in metastatic cancer cells and its ectopic overexpression in mouse mammary epithelial cells can induce mammary epithelial proliferation and tumorigenesis [27,29,30]. In addition, MTA1 serves as a transcriptional corepressor of estrogen receptor α (ERα) [31].…”

“…The RbAp46 and/or RbAp48 subunits were originally identified as proteins associated with the retinoblastoma (Rb) tumor suppressor [23], and they may function as structural proteins that provide interactive interfaces for other components of the Mi2/NuRD complex [20,24,25]. The Mi2/NuRD complex also contains one of the metastasis-associated (MTA) protein family members, MTA1, MTA2 or MTA3 [20,[26][27][28]. Each MTA member modifies the functional specificities of the Mi2/NuRD complexes relevant to its upstream and downstream signaling pathways and molecular targets.…”