MTA1 Interacts with MAT1, a Cyclin-dependent Kinase-activating Kinase Complex Ring Finger Factor, and Regulates Estrogen Receptor Transactivation Functions

Abstract

The transcriptional activity of estrogen receptor-␣ is controlled by coregulators. MTA1 (metastasis-associated protein 1) represses estrogen receptor-␣-driven transcription by recruiting histone deacetylases (HDACs) to the estrogen response element containing target gene chromatin in breast cancer cells. Using a yeast twohybrid screen with the MTA1 C-terminal domain as bait, we identified MAT1 (mé nage á trois 1) as an MTA1-binding protein. MAT1 is an assembly/targeting factor for cyclin-dependent kinase-activating kinase (CAK), which has been shown to functionally interact with general transcriptional factor TFIIH, a known inducer of ER transactivation. We show that estrogen signaling promotes nuclear translocation of MAT1 and that MTA1 interacts with MAT1 both in vitro and in vivo. The eukaryotic genome is compacted with histone and other proteins to form chromatin, which consists of repeating units of nucleosome (1, 2). Formation of nucleosomes and higher order chromatin structures can render the DNA inaccessible to transcription factors and complexes. For transcription factors to access DNA, the repressive chromatin structure needs to be remodeled. Dynamic alterations in the chromatin structure can facilitate or suppress the access of the transcription factors to nucleosomal DNA, leading to transcriptional regulation. One way to achieve this is through alterations in chromatin remodeling factors or in the acetylation state of nucleosomal histones (3-5). Acetylation of core histones occurs at lysine residues on the N-terminal tails of the histones, thus neutralizing the positive charge of the histone tails and decreasing their affinity for DNA. Hyperacetylated chromatin is generally associated with transcription activation, whereas hypoacetylated chromatin is associated with transcription repression (3-6).A number of recent studies have raised the possibility of a close connection between HDACs 1 and cancer. Because HDACmediated deacetylation of nucleosomal histones is known to be associated with transcriptional repression of some genes, it is being proposed that the deregulation of recruitment of HDACcontaining repressor complex to specific target promoters could serve as a potential mechanism by which these enzymes contribute to tumorigenesis. For example, MTA1 (metastasis-associated protein 1) represses estrogen receptor-␣ (ER)-driven transcription by recruiting HDAC to the ER response element (ERE)-containing target gene chromatin in breast cancer cells (7). The NuRD-70 polypeptide of nucleosome remodeling/ HDAC complex is identical to that of the MTA1 (8 -11). The MTA1 gene was initially identified by differential expression in rat mammary adenocarcinoma metastatic cells, and its expression has been shown to correlate well with the metastatic potential of several human cell lines and tumors (12).To better understand the cellular functions of MTA1 in breast cancer cells, we performed a yeast two-hybrid screen to clone MTA1-interacting proteins. One of several isolates was identified as MAT1 (ménage á troi...

Expression of MTA1 promotes motility and invasiveness of PANC-1 pancreatic carcinoma cells

“…The augmented expression contributes to enhanced histone deacetylase activity, inhibition of oestrogen-receptor element-driven gene transcription, and progression to an invasive phenotype. Moreover, it has been reported that MAT1 (ménage á trios 1), an assembly/targeting factor for cyclin-dependent kinase-activating kinase (CAK), is an MTA1-binding protein (Talukder et al, 2003). The results reported in the latter study suggest that MTA1 might inhibit CAK-induced oestrogen receptor transactivation function by recruiting histone deactylase.…”

Metastasis-associated Protein 1/Histone Deacetylase 4-Nucleosome Remodeling and Deacetylase Complex Regulates Phosphatase and Tensin Homolog Gene Expression and Function

“…Recruitment of the MTA1⅐HDAC4 Complex on the PTEN Promoter Inhibits PTEN Expression-To understand the molecular mechanism underlying the noted MTA1 repression of PTEN transcription, we carried out a ChIP analysis with HDAC2, a component of the MTA1 corepressor complex (29). However, we failed to detect any recruitment of HDAC2 onto the PTEN promoter (Fig.…”

“…Earlier studies have demonstrated that MTA1 forms a corepressor complex with HDAC1/2 and is recruited to the target gene promoters, thereby repressing gene transcription (29). For example, the MTA1⅐HDAC2 complex was identified as a transcriptional corepressor of number of tumor suppressor genes such as BRAC1, p21WAF1, and RNF144, where the MTA1⅐HDAC2 complex recruits onto their promoters and down-regulates the expression of these genes, leading to accelerated tumor growth and metastasis (32,41,42).…”

MTA1-mediated transcriptional repression of BRCA1 tumor suppressor gene

“…Recent data suggest that the Ets-2 transcription factor may play a role in the repression of the BRCA1 promoter (Baker et al, 2003). The notion that MTA1 might be a corepressor was merely speculative until the recent discovery that MTA1 associates with histone deacetylases (HDACs) and thereby helps to repress estrogen receptor-a (ERa) transactivation in breast cancer cells (Mazumdar et al, 2001;Talukder et al, 2003). Since the BRCA1 promoter contains an atypical estrogen-responsive element (ERE) (Xu et al, 1997), we hypothesized that MTA1 might play a role in BRCA1 repression.…”