MTA family of coregulators in nuclear receptor biology and pathology

Abstract

IntroductionMetastasis is a complex disease involving a series of events that includes stimulation or repression of numerous gene products in a coordinate manner, resulting in the invasion of neoplastic cells and detachment from the primary tumors, penetration into blood and lymphatics, arrest by adhesion at distant sites, extravasation, induction of angiogenesis, evasion of host antitumor responses, and growth at metastatic sites [Nicolson, 1988]. To identify the genes potentially involved in breast cancer invasion and metastasis, Toh et al. performed differential screening of a cDNA library of metastatic and nonmetastatic adenocarcinoma cell lines from rat mammary glands and cloned a novel gene known as the metastasis-associated tumor gene (mta1) [Toh et al., 1994]. Despite widespread overexpression of the MTA1 protein in human tumors, the molecular functions of the MTA family remained a mystery until the proteomic analysis of the nucleosome remodeling and deacetylation (NuRD) complex identified MTA1 and MTA2 as integral to the histone deacetylase (HDAC) complexes [Xue et al., 1998;Zhang et al., 1998], thus providing clues about the role of the MTA family of proteins in chromatin remodeling. MTA3, the third member of the MTA family, was identified as an estrogen-inducible gene product that forms a distinct Mi-2/NuRD complex [Fujita et al., 2003]. MTA1s, a naturally occurring variant of MTA1, was accidentally discovered by researchers pursuing the role of MTA1 in transcriptional regulation of estrogen receptor-α (ER) [Kumar et al., 2002]. MTA1s is generated by alternative splicing at a cryptic splice-site in exon 14, involving the deletion of 47 base pair nucleotides, and a frame-shift involving the addition of 33 unique amino acids with no homology among sequences from Genbank. The resulting MTA1s gene product lacks the C-terminal region of other MTA family members [Kumar et al., 2002]. Using a polyclonal antibody against purified zymogen granule membrane components from rat pancreas, researchers identified ZG29p, a cDNA coding for the 29-kDa protein, by immunoscreening a hormonally stimulated pancreas cDNA library. ZG29p is an N-terminal truncated form of MTA1, coded by the last seven exons of MTA1 and present in the zymogen granules of the pancreas. ZG29p mediates an interaction with amylase and is involved in condensation-sorting in the exocrine rat pancreas [Kleene et al., 2000]. Domain structure of the MTA familyMTA1 and MTA2 are polypeptides with molecular masses of approximately 80 kDa and 70 kDa, respectively, whereas MTA3 is smaller, approximately 65 kDa. Protein alignment homology of the human MTA proteins revealed 68% and 73% homology of MTA2 and MTA3, respectively, with MTA1. The highest homology was concentrated in the N-terminal half of the proteins, whereas the C-terminal regions of the MTA proteins were divergent (Figure 1A and [Manavathi and Kumar, 2007] has not yet been directly tested; it is currently hypothesized from studies of proteins containing such domains. For example, the BAH domain ...

High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer

“…This complex can interact with promoters containing estrogen-response elements to inhibit estrogen-driven transactivation. Unlike tamoxifen, which selectively modulates ER function and slows breast cancer growth, repression of ER-responsive promoters by HSF1 might contribute to progression in the manner suggested for the Lim domain only 4 (LMO4) protein (26) and the MTA1s ("short") variant of MTA1 (27,28). Repression of ER-driven transactivation by these proteins may contribute to the development of an ERnegative phenotype similar to that seen in aggressive ER-negative tumors.…”

Correlation between MTA2 overexpression and tumour progression in esophageal squamous cell carcinoma

“…The prognosis of patients with overexpression of MTA2 was poorer than that of patients with MTA2 underexpression. Cancer invasion and metastasis are complex processes that include alterations in cell adhesion, allowing transformed cells to invade and migrate (12)(13)(14). MTA proteins are physiologically expressed at only low levels in human tissue, except the testis (10).…”

Mechanism of MTA1 Protein Overexpression-linked Invasion

“…One of the targets of interest for MTA1 was HMMR. Because both MTA1 (25)(26)(27) and HMMR (10 -14, 16, 36, 37) are widely up-regulated genes in human cancers, we undertook this study to understand the biochemical basis of the noted MTA1-HMMR association. Western blot analysis of breast cancer cell lines ZR-75, MCF-7, and T47D revealed a positive correlation between the levels of MTA1 and HMMR proteins (Fig.…”

“…MTA1 executes its function on the target gene by recruiting either RNA polymerase II (pol II) or histone deacetylase to the target gene chromatin (21)(22)(23)(24). MTA1 is up-regulated in human cancers and also acts as an oncogene (25)(26)(27). MTA1 forms a coactiva-tion complex with c-Jun and pol II on FosB motif-containing chromatin and plays a pivotal role in invasion by repressing E-cadherin expression (28).…”