Physiological functions of MTA family of proteins

Sen, Nirmalya; Gui, B.; Kumar, Rakesh

doi:10.1007/s10555-014-9514-4

Cited by 41 publications

(33 citation statements)

References 58 publications

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“…presence of histone deacetylases (HDACs) (Bowen et al, 2004), but the presence of HDACs per se does not ensure transcriptional repression because studies on the NuRD interaction with the GATA-1/FOG-1 transcription factor complex support transcriptional activation (Miccio et al, 2010). At this time it is unclear if AhR recruitment of MTA2 occurs in the context of a complete NuRD complex capable of coactivation as described for GATA-1/FOG-1, or if MTA2 is functioning in an NuRD-independent capacity akin to that proposed for MTA1 (Sen et al, 2014). Kim et al (2014) recently demonstrated that two NuRD subunits, CHD4 and MTA2, associated constitutively with the DNA-bound CLOCK-BMAL1 to drive target gene expression, and that transcriptional repression only occurred once the negative regulator, PERIOD, recruited the remaining NuRD complex components to CLOCK-BMAL1 DNA binding sites.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation by Agonist-Specific Aryl Hydrocarbon Receptor Recruitment of Metastasis-Associated Protein 2 Selectively Induces Stanniocalcin 2 Expression

2017

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The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates a plethora of target genes. Historically, the AhR has been studied as a regulator of xenobiotic metabolizing enzyme genes, notably cytochrome P4501A1 encoded by CYP1A1, in response to the exogenous prototypical ligand 2,3,7,8-tetrachlorodibenzo--dioxin (TCDD). AhR activity depends on its binding to the xenobiotic response element (XRE) in partnership with the AhR nuclear translocator (Arnt). Recent studies identified stanniocalcin 2 (Stc2) as a novel AhR target gene responsive to the endogenous AhR agonist cinnabarinic acid (CA). CA-dependent AhR-XRE-mediated Stc2 upregulation is responsible for cytoprotection against ectoplasmic reticulum/oxidative stress-induced apoptosis both in vitro and in vivo. Significantly, CA but not TCDD induces expression of Stc2 in hepatocytes. In contrast to TCDD, CA is unable to induce the CYP1A1 gene, thus revealing an AhR agonist-specific mutually exclusive dichotomous transcriptional response. Studies reported here provide a mechanistic explanation for this differential response by identifying an interaction between the AhR and the metastasis-associated protein 2 (MTA2). Moreover, the AhR-MTA2 interaction is CA-dependent and results in MTA2 recruitment to the Stc2 promoter, concomitant with agonist-specific epigenetic modifications targeting histone H4 lysine acetylation. The results demonstrate that histone H4 acetylation is absolutely dependent on CA-induced AhR and MTA2 recruitment to the Stc2 regulatory region and induced Stc2 gene expression, which in turn confers cytoprotection to liver cells exposed to chemical insults.

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Section: Discussionmentioning

confidence: 99%

Epigenetic Regulation by Agonist-Specific Aryl Hydrocarbon Receptor Recruitment of Metastasis-Associated Protein 2 Selectively Induces Stanniocalcin 2 Expression

2017

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“…Over the years, the MTA family members have emerged as one of the most important regulatory molecules with both redundant and non-redundant activities in both physiological and cancer cells (Sen et al, 2014a, Sen et al, 2014b). A large body of work over the years suggests that the MTA family members regulate numerous cellular pathways with roles in cancer progression and metastasis (Li and Kumar, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…A large body of work over the years suggests that the MTA family members regulate numerous cellular pathways with roles in cancer progression and metastasis (Li and Kumar, 2015). However, because MTA family members are ubiquitously expressed and natural levels of MTA family members are equally important for several essential physiological functions (Sen et al, 2014a), the authors believe the MTA family members may also follow a nomenclature that is based on their structural elements, rather than the current nomenclature derived from the historical cloning of the founding member MTA1 - as a differential expressed gene from rat metastatic mammary gland tumors (Toh et al, 1994). However, this is more of a philosophical point of continuing scientific debate as the functions of MTA family members are independent of what we name these proteins.…”

Section: Introductionmentioning

confidence: 99%

Structure, expression and functions of MTA genes

Kumar

Wang

2016

Gene

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Metastatic associated proteins (MTA) are integrators of upstream regulatory signals with the ability to act as master coregulators for modifying gene transcriptional activity. The MTA family includes three genes and multiple alternatively spliced variants. The MTA proteins neither have their own enzymatic activity nor have been shown to directly interact with DNA. However, MTA proteins interact with a variety of chromatin remodeling factors and complexes with enzymatic activities for modulating the plasticity of nucleosomes, leading to the repression or derepression of target genes or other extra-nuclear and nucleosome remodeling and histone deacetylase (NuRD)-complex independent activities. The functions of MTA family members are driven by the steady state levels and subcellular localization of MTA proteins, the dynamic nature of modifying signals and enzymes, the structural features and post-translational modification of protein domains, interactions with binding proteins, and the nature of the engaged and resulting features of nucleosomes in the proximity of target genes. In general, MTA1 and MTA2 are the most upregulated genes in human cancer and correlate well with aggressive phenotypes, therapeutic resistance, poor prognosis and ultimately, unfavorable survival of cancer patients. Here we will discuss the structure, expression and functions of the MTA family of genes in the context of cancer cells.

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“…In this regard, the target molecule MTA1 is a well studied nuclear receptor coregulator in malignant disorders and has been shown to be induced in response to growth factors (32). Several recent studies have reported the tissue-specific functions of MTA1 and have been shown to act both as a coactivator and a corepressor depending on the tissue type (42). In view of this, we tested the idea whether MTA1 could be up-regulated in the dopaminergic neurons by growth factors, thereby increasing the levels of TH.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanism of Regulation of MTA1 Expression by Granulocyte Colony-stimulating Factor

Kumar

Jagadeeshan

Subramanian

et al. 2016

Journal of Biological Chemistry

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Parkinson disease (PD) is a neurodegenerative disorder with loss of dopaminergic neurons of the brain, which results in insufficient synthesis and action of dopamine. Metastasis-associated protein 1 (MTA1) is an upstream modulator of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, and hence MTA1 plays a significant role in PD pathogenesis. To impart functional and clinical significance to MTA1, we analyzed MTA1 and TH levels in the substantia nigra region of a large cohort of human brain tissue samples by Western blotting, quantitative PCR, and immunohistochemistry. Our results showed that MTA1 and TH levels were significantly down-regulated in PD samples as compared with normal brain tissue. Correspondingly, immunohistochemistry analysis for MTA1 in substantia nigra sections revealed that 74.1% of the samples had a staining intensity of <6 in the PD samples as compared with controls, 25.9%, with an odds ratio of 8.54. Because of the clinical importance of MTA1 established in PD, we looked at agents to modulate MTA1 expression in neuronal cells, and granulocyte colony-stimulating factor (G-CSF) was chosen, due to its clinically proven neurogenic effects. Treatment of the human neuronal cell line KELLY and acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model with G-CSF showed significant induction of MTA1 and TH with rescue of phenotype in the mouse model. Interestingly, the observed induction of TH was compromised on silencing of MTA1. The underlying molecular mechanism of MTA1 induction by G-CSF was proved to be through induction of c-Fos and its recruitment to the MTA1 promoter. Parkinson disease (PD)4 is an idiopathic degenerative disorder of the central nervous system characterized by slow and decreased movement, pill-rolling tremor, and postural instability, and it is primarily caused by dopamine deficiency (1, 2). The rate-limiting enzyme for dopamine synthesis is tyrosine hydroxylase (TH) (3). Currently, there is no cure for PD, and patients are usually given drugs that provide symptomatic relief (4). Recently, it was shown that G-CSF enhances recovery in the mouse model of PD, and hence the G-CSF receptor might be a novel target for modifying the disease process in PD (5, 6). It is well documented that a consistent abnormality in PD is degeneration of dopaminergic neurons in SN leading to a reduction of striatal dopamine levels (7). TH catalyzes the formation of L-hydroxyphenylalanine, the rate-limiting step in the biosynthesis of dopamine. Thus, efficient treatment strategy for PD could be based on correcting or bypassing the TH enzyme deficiency or its downstream enzymes essential for catecholamine synthesis (8). For this, elucidation of the molecular mechanism of human TH gene regulation is very essential. Also, epigenetic profiling of the human TH promoter suggests that chromatin remodeling could have a significant impact in conferring tissue-specific gene expression of the human TH gene (9); however, its specific role in TH transcription remains poorly understood...

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Physiological functions of MTA family of proteins

Cited by 41 publications

References 58 publications

Epigenetic Regulation by Agonist-Specific Aryl Hydrocarbon Receptor Recruitment of Metastasis-Associated Protein 2 Selectively Induces Stanniocalcin 2 Expression

Epigenetic Regulation by Agonist-Specific Aryl Hydrocarbon Receptor Recruitment of Metastasis-Associated Protein 2 Selectively Induces Stanniocalcin 2 Expression

Structure, expression and functions of MTA genes

Molecular Mechanism of Regulation of MTA1 Expression by Granulocyte Colony-stimulating Factor

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