Regulation of RE1 Protein Silencing Transcription Factor (REST) Expression by HIP1 Protein Interactor (HIPPI)

Datta, Moumita; Bhattacharyya, Nitai P.

doi:10.1074/jbc.m111.265173

Cited by 19 publications

(13 citation statements)

References 41 publications

(71 reference statements)

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“…The method of Luciferase reporter assay was previously described ( 13 ). LoVo cells were cultured in a 48-well plates in advance and transfected with 0.23 μ g of FAM172A promoter plasmids and 0.02 μ g of endogenous control phRL-TK plasmids using jetPRIME™ (Polyplus Transfection, Illkirch, France) in accordance with the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

FAM172A modulates apoptosis and proliferation of colon cancer cells via STAT1 binding to its promoter

Qian

Zhang

et al. 2015

Oncology Reports

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In our previous study, low expression of FAM172A protein was found in colon cancer tissues. This research was planned to explore the functions of FAM172A gene and examine the mechanisms of its transcriptional regulation. Firstly, flow cytometry showed that FAM172A inhibited proliferation and promoted apoptosis and differentiation of colon cancer cells. Then through continuous truncation, we identified the minimal functional promoter region of FAM172A. Subsequently, we found that STAT1, as a transcription factor, could bind to the minimal FAM172A promoter, as evaluated using Chromatin immunoprecipitation (ChIP) and Electrophoreticmobility shift assay (EMSA). The results of Western blot analysis and qRT-PCR indicated that STAT1 was able to upregulate the expression of FAM172A. Our results showed that FAM172A could suppress proliferation of colon cancer cells, and STAT1 could bind to the minimum promoter region of FAM172A and upregulated the expression of FAM172A. These results may provide advanced insights into the functions of FAM172A and its regulatory mechanisms.

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Section: Methodsmentioning

confidence: 99%

FAM172A modulates apoptosis and proliferation of colon cancer cells via STAT1 binding to its promoter

Qian

Zhang

et al. 2015

Oncology Reports

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“…In Huntington´s disease models, mHtt further triggers a pathogenic cascade involving Sp1 activation, which leads to the upregulation of REST [22]. The weak interaction of mHtt with HIP1 protein also results in increased nuclear accumulation of HIPPI and HIP1, leading to occupancy of HIPPI at the REST promoter, triggering its transcriptional activation and directly repress REST target genes [23]. Hence, these genes are intimately involved in the regulation of many cardinal cellular processes for neuronal identity and function [24], and REST contributes to HD pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

The interaction between RE1-silencing transcription factor (REST) and heat shock protein 90 as new therapeutic target against Huntington’s disease

2019

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The wild type huntingtin protein (Htt), supports the production of brain-derived neurotrophic factor (BDNF), a survival factor for striatal neurons, through cytoplasmic sequestering of RE-1silencing transcription factor (REST). In Huntington´s Disease an inherited degenerative disease, caused by a CAG expansion in the 5´coding region of the gene, the mutant huntingtin protein (mHtt), causes that REST enters pathologically into the nucleus of cells, resulting in the repression of neuronal genes including BDNF, resulting in the progressive neuronal death. It has been reported that Htt associates with Hsp90 and this interaction is involved in regulation of huntingtin aggregation. Discovering mechanisms to reduce the cellular levels of mutant huntingtin and REST provide promising strategies for treating Huntington disease. Here, we use the yeast two-hybrid system to show that N-terminus or REST interacts with the heat shock protein 90 (Hsp90) and identifies REST as an Hsp90 Client Protein. To assess the effects of Hsp90 we used antisense oligonucleotide, and evaluated the levels mHtt and REST levels. Our results show that direct knockdown of endogenous Hsp90 significantly reduces the levels of REST and mutant Huntingtin, decreased the percentage of cells with mHtt in nucleus and rescued cells from mHtt-induced cellular cytotoxicity. Additionally Hsp90–specific inhibitors geldanamicyn and PUH71 dramatically reduced mHtt and REST levels, thereby providing neuroprotective activity. Our data show that Hsp90 is necessary to maintain the levels of REST and mHtt, which suggests that the interactions between Hsp90-REST and Hsp90-Huntingtin could be potential therapeutic targets in Huntington's disease.

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“…Building on studies using the R6/2 HD mouse model and HD patient specimens, it has been postulated that the mHTT protein produces one of its major effects through aberrant REST OE in the neuronal nucleus, presumably through the release of REST from its cytoplasmic HTT-REST complex leading to the accumulation of REST in the nucleus where it represses its target genes 30 – 32 . Independently, the huntingtin interacting protein 1 protein interactor (HIPPI) has been found to directly activate REST gene transcription in an HD model 33 . In addition, decreased levels of miR-9, which targets REST, have also been found in HD patient cortices 34 .…”

Section: Introductionmentioning

confidence: 99%

REST overexpression in mice causes deficits in spontaneous locomotion

Lü

Marisetty

Liu

et al. 2018

Sci Rep

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Overexpression of REST has been implicated in brain tumors, ischemic insults, epilepsy, and movement disorders such as Huntington’s disease. However, owing to the lack of a conditional REST overexpression animal model, the mechanism of action of REST overexpression in these disorders has not been established in vivo. We created a REST overexpression mouse model using the human REST (hREST) gene. Our results using these mice confirm that hREST expression parallels endogenous REST expression in embryonic mouse brains. Further analyses indicate that REST represses the dopamine receptor 2 (Drd2) gene, which encodes a critical nigrostriatal receptor involved in regulating movement, in vivo. Overexpression of REST using Drd2-Cre in adult mice results in increased REST and decreased DRD2 expression in the striatum, a major site of DRD2 expression, and phenocopies the spontaneous locomotion deficits seen upon global DRD2 deletion or specific DRD2 deletion from indirect-pathway medium spiny neurons. Thus, our studies using this mouse model not only reveal a new function of REST in regulating spontaneous locomotion but also suggest that REST overexpression in DRD2-expressing cells results in spontaneous locomotion deficits.

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Regulation of RE1 Protein Silencing Transcription Factor (REST) Expression by HIP1 Protein Interactor (HIPPI)

Cited by 19 publications

References 41 publications

FAM172A modulates apoptosis and proliferation of colon cancer cells via STAT1 binding to its promoter

FAM172A modulates apoptosis and proliferation of colon cancer cells via STAT1 binding to its promoter

The interaction between RE1-silencing transcription factor (REST) and heat shock protein 90 as new therapeutic target against Huntington’s disease

REST overexpression in mice causes deficits in spontaneous locomotion

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