Ataxin 1, a
            <i>SCA1</i>
            neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors

Tsai, Chih Cheng; Kao, Hung Ying; Mitzutani, Akifumi; Banayo, Ester; Rajan, Harini; McKeown, Michael; Evans, Ronald M.

doi:10.1073/pnas.0400615101

Cited by 140 publications

(139 citation statements)

References 52 publications

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“…The gene ATXN1, which is mutated to contain an expanded CAG trinucleotide repeat in spinocerebellar ataxia-1, encodes for the protein Ataxin 1. Ataxin 1 is detected in various brain regions and in non-neuronal tissues, such as the heart, skeletal muscle and liver (Servadio et al, 1995;Tsai et al, 2004). Stanniocalcin1, encoded by STC1 gene, is a glycoprotein hormone and it has a role in many physiological processes, including bone development, reproduction, wound healing, angiogenesis and modulation of inflammatory response (Ishibashi and Imai, 2002;Chang et al, 2003).…”

Section: Atxn1 and Stc1 Are Targets Of Mir-101bmentioning

confidence: 99%

Regulation of microRNA expression by HMGA1 proteins

et al. 2009

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The High Mobility Group proteins HMGA1 are nuclear architectural factors that play a critical role in a wide range of biological processes. Since recent studies have identified the microRNAs (miRNAs) as important regulators of gene expression, modulating critical cellular functions such as proliferation, apoptosis and differentiation, the aim of our work was to identify the miRNAs that are physiologically regulated by HMGA1 proteins. To this purpose, we have analysed the miRNA expression profile of mouse embryonic fibroblasts (MEFs) carrying two, one or no Hmga1 functional alleles using a microarray (miRNA microarray). By this approach, we found a miRNA expression profile that differentiates Hmga1-null MEFs from the wild-type ones. In particular, a significant decrease in miR-196a-2, miR-101b, miR-331 and miR-29a was detected in homozygous Hmga1-knockout MEFs in comparison with wild-type cells. Consistently, these miRNAs are downregulated in most of the analysed tissues of Hmga1-null mice in comparison with the wild-type mice. ChIP assay shows that HMGA1 is able to bind regions upstream of these miRNAs. Moreover, we identified the HMGA2 gene product as a putative target of miR-196a-2, suggesting that HMGA1 proteins are able to downregulate the expression of the other member of the HMGA family through the regulation of the miR-196a-2 expression. Finally, ATXN1 and STC1 gene products have been identified as targets of miR-101b. Therefore, it is reasonable to hypothesize that HMGA1 proteins are involved in several functions by regulating miRNA expression.

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Section: Atxn1 and Stc1 Are Targets Of Mir-101bmentioning

confidence: 99%

Regulation of microRNA expression by HMGA1 proteins

et al. 2009

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“…Two groups have confirmed the ability of ataxin-1, independent of glutamine repeat length, to repress transcription when tethered to artificial promoters (Tsai et al 2004;Okazawa et al 2002). In 2002, one of these groups showed the ability of mutant ataxin-1[82Q] to repress transcription was enhanced in the presence of PQBP-1 (polyQ-binding protein) (Okazawa et al 2002).…”

Section: Sca1: Corepressors and Remodeling At Sites Of Transcriptionmentioning

confidence: 98%

“…In addition to demonstrating ataxin-1's ability to mediate transcriptional repression and bind chromosomes, Ron Evans's group (Tsai et al 2004) showed an interaction of ataxin-1 with the corepressors, silencing mediator of retinoid and thyroid hormone receptors (SMRT) and histone deacetylase 3 (HDAC3). There was enhanced Drosophila eye neurodegeneration when SMRTER (Drosophila homolog of SMRT) and mutant ataxin-1[82Q] flies were crossed compared with mutant ataxin-1[82Q] alone (Tsai et al 2004).…”

Section: Sca1: Corepressors and Remodeling At Sites Of Transcriptionmentioning

confidence: 99%

“…There was enhanced Drosophila eye neurodegeneration when SMRTER (Drosophila homolog of SMRT) and mutant ataxin-1[82Q] flies were crossed compared with mutant ataxin-1[82Q] alone (Tsai et al 2004). The investigators concluded that perturbation of corepressor-dependent transcriptional pathways by mutant ataxin-1[82Q] contributes to SCA1 pathogenesis (Tsai et al 2004).…”

Section: Sca1: Corepressors and Remodeling At Sites Of Transcriptionmentioning

confidence: 99%

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Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle

Riley¹,

Orr²

2006

Genes Dev.

132

106

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The polyglutamine disorders are a class of nine neurodegenerative disorders that are inherited gain-of-function diseases caused by expansion of a translated CAG repeat. Even though the disease-causing proteins are widely expressed, specific collections of neurons are more susceptible in each disease, resulting in characteristic patterns of pathology and clinical symptoms. One hypothesis poses that altered protein function is fundamental to pathogenesis, with protein context of the expanded polyglutamine having key roles in diseasespecific processes. This review will focus on the role of the disease-causing polyglutamine proteins in gene transcription and the extent to which the mutant proteins induce disruption of transcription.One of the intriguing developments in human genetics is the identification of a mutational mechanism apparently unique to the human genome, the expansion of unstable nucleotide repeats (Gatchel and Zoghbi 2005). Depending on the genetic context of the unstable repeat, the pathogenic mechanism underlying the disorder can be either a loss-of-function or gain-of-function mutation operating at either the RNA or protein level. A subclass of the unstable repeat disorders is caused by the expansion of an unstable CAG trinucleotide repeat located within the protein encoding region such that the repeat is translated into a stretch of glutamine residues; i.e., the polyglutamine diseases. Although rare as a group, the polyglutamine disorders represent the most common form of inherited neurodegenerative disease. At present, nine disorders make up this class of neurodegenerative disease (Table 1). Initially, it was argued that the genetic similarities among these disorders strongly supported the hypothesis that these disorders shared a common mechanism of pathogenesis entirely dependent on the toxic properties of the polyglutamine tract. This typically centered on the enhanced ability of polyglutamine peptides to form intranuclear aggregates/inclusions (Ross and Poirer 2004). The presence of these aggregates/ inclusions within the nuclei of affected neurons focused attention on the nucleus as the subcellular site important in pathogenesis. After much study, the concept of large aggregates/inclusions of mutant polyglutamine as the pathogenic species has become suspect (Arrasate et al. 2004). However, for many of the polyglutamine disorders, understanding events in the nucleus still remains crucial for comprehending pathogenesis.Expansion of the polyglutamine tract is the trigger for pathogenesis. Yet, it likely does so by acting in concert with the other amino acids of the "host" protein (Orr 2001). This point is nicely illustrated by studies on SCA1 and AR/SBMA. In the case of SCA1, replacing single amino acids in ataxin-1 outside of its polyglutamine tract dramatically reduced the ability of mutant ataxin-1 (ataxin-1[82Q]) to cause disease in vivo (Klement et al. 1998;Emamian et al. 2003). In SBMA, androgen binding to the ligand-binding region in AR is critical for pathogenesis (Katsuno et al. 2002(K...

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“…A self-association region of the non-expanded protein was mapped in the centre of the protein and identified to overlap the only certified globular domain of the otherwise PeerJ PrePrints | http://dx.doi.org/10.7287/peerj.preprints.259v1 | CC-BY 4.0 Open Access | received: , published: 27 Feb 2014 mostly unstructured protein, the AXH domain that spans residues 562-689 (SMART SM00536) (Burright et al, 1997;de Chiara et al, 2003). This motif is functionally very important as it is involved in transcriptional regulation as well as in the RNA-binding activity of ataxin-1 (Matilla et al, 1997;Okazawa et al 2002;Tsai et al, 2004;de Chiara et al, 2003;de Chiara et al, 2005;Mizutani et al, 2005;Tsuda et al 2005;Lam et al, 2006;Serra et al, 2006;Goold et al, 2007;Lee et al 2011). AXH is also necessary and sufficient for the majority of the known interactions of ataxin-1 with other proteins, most of which are transcriptional regulators (Tsai et al, 2004;Tsuda et al 2005;Lam et al, 2006;Goold et al, 2007;Serra et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Mapping the self-association domains of ataxin-1: Identification of novel non overlapping motifs

Menon

Soong

Chiara

et al. 2014

Preprint

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The neurodegenerative spinocerebellar ataxia type 1 (SCA1) is caused by aggregation and misfolding of the ataxin-1 protein. While the pathology correlates with mutations that lead to expansion of a polyglutamine tract in the protein, other regions contribute to the aggregation process as also non-expanded ataxin-1 is intrinsically aggregation-prone and forms nuclear foci in cell. Here, we have used a combined approach based on FRET analysis, confocal microscopy and in vitro techniques to map aggregation-prone regions other than polyglutamine and to establish the importance of dimerization in self-association/foci formation. Identification of aggregation-prone regions other than polyglutamine could greatly help the development of SCA1 treatment more specific than that based on targeting the low complexity polyglutamine region.PeerJ PrePrints | http://dx.doi.org/10.7287/peerj.preprints.259v1 | CC-BY 4.0

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Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors

Cited by 140 publications

References 52 publications

Regulation of microRNA expression by HMGA1 proteins

Regulation of microRNA expression by HMGA1 proteins

Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle

Mapping the self-association domains of ataxin-1: Identification of novel non overlapping motifs

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