Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PML fuses with retinoic acid receptor alpha (RARalpha) in the t(15;17) translocation that causes acute promyelocytic leukemia (APL). In addition to localizing diffusely throughout the nucleoplasm, PML mainly resides in discrete nuclear structures known as PML oncogenic domains (PODs), which are disrupted in APL and spinocellular ataxia cells. We isolated the Fas-binding protein Daxx as a PML-interacting protein in a yeast two-hybrid screen. Biochemical and immunofluorescence analyses reveal that Daxx is a nuclear protein that interacts and colocalizes with PML in the PODs. Reporter gene assay shows that Daxx drastically represses basal transcription, likely by recruiting histone deacetylases. PML, but not its oncogenic fusion PML-RARalpha, inhibits the repressor function of Daxx. In addition, SUMO-1 modification of PML is required for sequestration of Daxx to the PODs and for efficient inhibition of Daxx-mediated transcriptional repression. Consistently, Daxx is found at condensed chromatin in cells that lack PML. These data suggest that Daxx is a novel nuclear protein bearing transcriptional repressor activity that may be regulated by interaction with PML.
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PMID:Sequestration and inhibition of Daxx-mediated transcriptional repression by PML. 1066 54

Polyglutamine diseases include at least 9 neurodegenerative disorders: Huntington's disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinobulbar muscular atrophy (SBMA), and spinocerebellar ataxia (SCA) type: 1-3, 6-7 and 17, each caused by a CAG-trinucleotide repeat expansion in a different gene. The poly-CAG sequence is translated into a polyglutamine stretch in the respective proteins. This review discusses mutual molecular features of polyglutamine diseases. The formation of intranuclear inclusions, recruitment of physiological polyglutamine proteins as well as a potential role of molecular chaperones, capsases, and inhibition of histone acetyltransferases-depended transcription in cellular pathogenesis are considered.
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PMID:[Molecular biology of polyglutamine diseases]. 1266 7

DNA damage induces cell cycle arrest and DNA repair or apoptosis in proliferating cells. Terminally differentiated cells are permanently withdrawn from the cell cycle and partly resistant to apoptosis. To investigate the effects of genotoxic agents in postmitotic cells, we compared DNA damage-activated responses in mouse and human proliferating myoblasts and their differentiated counterparts, the myotubes. DNA double-strand breaks caused by ionizing radiation (IR) induced rapid activating autophosphorylation of ataxia-teleangiectasia-mutated (ATM), phosphorylation of histone H2AX, recruitment of repair-associated proteins MRE11 and Nbs1, and activation of Chk2 in both myoblasts and myotubes. However, IR-activated, ATM-mediated phosphorylation of p53 at serine 15 (human) or 18 (mouse) [Ser15(h)/18(m)], and apoptosis occurred in myoblasts but was impaired in myotubes. This phosphorylation could be enforced in myotubes by the anthracycline derivative doxorubicin, leading to selective activation of proapoptotic genes. Unexpectedly, the abundance of autophosphorylated ATM was indistinguishable after exposure of myotubes to IR (10 Gy) or doxorubicin (1 microM/24 h) despite efficient phosphorylation of p53 Ser15(h)/18(m), and apoptosis occurred only in response to doxorubicin. These results suggest that radioresistance in myotubes might reflect a differentiation-associated, pathway-selective blockade of DNA damage signaling downstream of ATM. This mechanism appears to preserve IR-induced activation of the ATM-H2AX-MRE11/Rad50/Nbs1 lesion processing and repair pathway yet restrain ATM-p53-mediated apoptosis, thereby contributing to life-long maintenance of differentiated muscle tissues.
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PMID:Differentiation-induced radioresistance in muscle cells. 1522 36

Huntington's disease can be used as a model to study neurodegenerative disorders caused by aggregation-prone proteins. It has been proposed that the entrapment of transcription factors in aggregates plays an important role in pathogenesis. We now report that the transcriptional activity of CBP is already repressed in the early time points by soluble mutant huntingtin, whereas the histone acetylase activity of CBP/p300 is gradually diminished over time. Mutant huntingtin bound much stronger to CBP than normal huntingtin, possibly contributing to repression. Especially at the later time points, CBP protein level was gradually reduced via the proteasome pathway. In sharp contrast, p300 was unaffected by mutant huntingtin. This selective degradation of CBP was absent in spinocerebellar ataxia 3. Thus, mutant huntingtin specifically affects CBP and not p300 both at the early and later time points, via multiple mechanisms. In addition to the reduction of CBP, also the altered ratio of these closely related histone acetyltransferases may affect chromatin structure and transcription and thus contribute to neurodegeneration.
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PMID:Mutant huntingtin represses CBP, but not p300, by binding and protein degradation. 1645 24

Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive neurodegenerative disease caused by polyglutamine expansion within the Atrophin-1 protein. To study the mechanism of this disease and to test potential therapeutic methods, we established Atro-118Q transgenic mice, which express in neurons a mutant human Atrophin-1 protein that contains an expanded stretch of 118 glutamines. Consistent with the results from previous studies on transgenic mice that expressed mutant Atrophin-1 with 65 glutamines, Atro-118Q mice exhibited several neurodegenerative phenotypes that are commonly seen in DRPLA patients, including ataxia, tremors, and other motor defects. Overexpression of wild-type human Atrophin-1 could not rescue the motor and survival defects in Atro-118Q mice, indicating that the mutant protein with polyglutamine expansion does not simply function in a dominant negative manner. Biochemical analysis of Atro-118Q mice revealed hypoacetylation of histone H3 in brain tissues and thus suggested that global gene repression is an underlying mechanism for neurodegeneration in this mouse model. We further show that intraperitoneal administration of sodium butyrate, a histone deacetylase inhibitor, ameliorated the histone acetylation defects, significantly improved motor performance, and extended the average life span of Atro-118Q mice. These results support the hypothesis that transcription deregulation plays an important role in the pathogenesis of polyglutamine expansion diseases and suggest that reversion of transcription repression with small molecules such as sodium butyrate is a feasible approach to treating DRPLA symptoms.
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PMID:Sodium butyrate ameliorates histone hypoacetylation and neurodegenerative phenotypes in a mouse model for DRPLA. 1640 96

Huntington's disease can be used as a model to study neurodegenerative disorders caused by aggregation-prone proteins. It has been proposed that the entrapment of transcription factors in aggregates plays an important role in pathogenesis. We now report that the transcriptional activity of CBP is already repressed in the early time points by soluble mutant huntingtin, whereas the histone acetylase activity of CBP/p300 is gradually diminished over time. Mutant huntingtin bound much stronger to CBP than normal huntingtin, possibly contributing to repression. Especially at the later time points, CBP protein level was gradually reduced via the proteasome pathway. In sharp contrast, p300 was unaffected by mutant huntingtin. This selective degradation of CBP was absent in spinocerebellar ataxia 3. Thus, mutant huntingtin specifically affects CBP and not p300 both at the early and later time points, via multiple mechanisms. In addition to the reduction of CBP, also the altered ratio of these closely related histone acetyl transferases may affect chromatin structure and transcription and thus contribute to neurodegeneration.
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PMID:Mutant huntingtin represses CBP, but not p300, by binding and protein degradation. 1599 95

Telomeres are specialized structures at the ends of chromosomes that consist of tandem repeats of the DNA sequence TTAGGG and several proteins that protect the DNA and regulate the plasticity of the telomeres. The telomere-associated protein TRF2 (telomeric repeat binding factor 2) is critical for the control of telomere structure and function; TRF2 dysfunction results in the exposure of the telomere ends and activation of ATM (ataxia telangiectasin mutated)-mediated DNA damage response. Recent findings suggest that telomere attrition can cause senescence or apoptosis of mitotic cells, but the function of telomeres in differentiated neurons is unknown. Here, we examined the impact of telomere dysfunction via TRF2 inhibition in neurons (primary embryonic hippocampal neurons) and mitotic neural cells (astrocytes and neuroblastoma cells). We demonstrate that telomere dysfunction induced by adenovirus-mediated expression of dominant-negative TRF2 (DN-TRF2) triggers a DNA damage response involving the formation of nuclear foci containing phosphorylated histone H2AX and activated ATM in each cell type. In mitotic neural cells DN-TRF2 induced activation of both p53 and p21 and senescence (as indicated by an up-regulation of beta-galactosidase). In contrast, in neurons DN-TRF2 increased p21, but neither p53 nor beta-galactosidase was induced. In addition, TRF2 inhibition enhanced the morphological, molecular and biophysical differentiation of hippocampal neurons. These findings demonstrate divergent molecular and physiological responses to telomere dysfunction in mitotic neural cells and neurons, indicate a role for TRF2 in regulating neuronal differentiation, and suggest a potential therapeutic application of inhibition of TRF2 function in the treatment of neural tumors.
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PMID:TRF2 dysfunction elicits DNA damage responses associated with senescence in proliferating neural cells and differentiation of neurons. 1653 55

Ataxin-3 (AT3), the disease protein in spinocerebellar ataxia type 3 (SCA3), has been associated with the ubiquitin-proteasome system and transcriptional regulation. Here we report that normal AT3 binds to target DNA sequences in specific chromatin regions of the matrix metalloproteinase-2 (MMP-2) gene promoter and represses transcription by recruitment of the histone deacetylase 3 (HDAC3), the nuclear receptor corepressor (NCoR), and deacetylation of histones bound to the promoter. Both normal and expanded AT3 physiologically interacted with HDAC3 and NCoR in a SCA3 cell model and human pons tissue; however, normal AT3-containing protein complexes showed increased histone deacetylase activity, whereas expanded AT3-containing complexes had reduced deacetylase activity. Consistently, histone analyses revealed an increased acetylation of total histone H3 in expanded AT3-expressing cells and human SCA3 pons. Expanded AT3 lost the repressor function and displayed altered DNA/chromatin binding that was not associated with recruitment of HDAC3, NCoR, and deacetylation of the promoter, allowing aberrant MMP-2 transcription via the transcription factor GATA-2. For transcriptional repression normal AT3 cooperates with HDAC3 and requires its intact ubiquitin-interacting motifs (UIMs), whereas aberrant transcriptional activation by expanded AT3 is independent of the UIMs but requires the catalytic cysteine of the ubiquitin protease domain. These findings demonstrate that normal AT3 binds target promoter regions and represses transcription of a GATA-2-dependent target gene via formation of histone-deacetylating repressor complexes requiring its UIM-associated function. Expanded AT3 aberrantly activates transcription via its catalytic site and loses the ability to form deacetylating repressor complexes on target chromatin regions.
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PMID:Ataxin-3 represses transcription via chromatin binding, interaction with histone deacetylase 3, and histone deacetylation. 1707 77

The leucine-rich acidic nuclear protein (LANP) belongs to the INHAT family of corepressors that inhibits histone acetyltransferases. The mechanism by which LANP restricts its repression to specific genes is unknown. Here, we report that LANP forms a complex with transcriptional repressor E4F and modulates its activity. As LANP interacts with ataxin 1--a protein mutated in the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1)--we tested whether ataxin 1 can alter the E4F-LANP interaction. We show that ataxin 1 relieves the transcriptional repression induced by the LANP-E4F complex by competing with E4F for LANP. These results provide the first functional link, to our knowledge, between LANP and ataxin 1, and indicate a potential mechanism for the transcriptional aberrations observed in SCA1.
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PMID:The role of LANP and ataxin 1 in E4F-mediated transcriptional repression. 1755 14

Expanded CAG repeat tracts are the cause of at least a dozen neurodegenerative disorders. In humans, long CAG repeats tend to expand during transmissions from parent to offspring, leading to an earlier age of disease onset and more severe symptoms in subsequent generations. Here, we show that the maintenance DNA methyltransferase Dnmt1, which preserves the patterns of CpG methylation, plays a key role in CAG repeat instability in human cells and in the male and female mouse germlines. SiRNA knockdown of Dnmt1 in human cells destabilized CAG triplet repeats, and Dnmt1 deficiency in mice promoted intergenerational expansion of CAG repeats at the murine spinocerebellar ataxia type 1 (Sca1) locus. Importantly, Dnmt1(+/-) SCA1 mice, unlike their Dnmt1(+/+) SCA1 counterparts, closely reproduced the intergenerational instability patterns observed in human SCA1 patients. In addition, we found aberrant DNA and histone methylation at sites within the CpG island that abuts the expanded repeat tract in Dnmt1-deficient mice. These studies suggest that local chromatin structure may play a role in triplet repeat instability. These results are consistent with normal epigenetic changes during germline development contributing to intergenerational instability of CAG repeats in mice and in humans.
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PMID:Dnmt1 deficiency promotes CAG repeat expansion in the mouse germline. 1825 47


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