Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription

Shimohata, Takayoshi; Nakajima, Takeshi; Yamada, Mitsunori; Uchida, Chiharu; Onodera, Osamu; Naruse, Satoshi; Kimura, Tetsuya; Koide, Reiji; Nozaki, Kenkichi; Sano, Yuichi; Ishiguro, Hiroshi; Sakoe, Kumi; Ooshima, Takayuki; Sato, Aki; Ikeuchi, Takeshi; Oyake, Mutsuo; Sato, Toshiya; Aoyagi, Yasuyuki; Hozumi, Isao; Nagatsu, Toshiharu; Takiyama, Yoshihisa; Nishizawa, Masatoyo; Goto, Jun; Kanazawa, Ichiro; Davidson, Irwin; Tanese, Naoko; Takahashi, Hitoshi; Tsuji, Shoji

doi:10.1038/79139

Cited by 379 publications

(246 citation statements)

References 48 publications

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“…CBP) from chromosomes. 2,3 The subsequent suppression of histone acetylation decreases cellular transcriptional activities, and these changes are implicated to cause polyQ toxicity. Based on this hypothesis, the maintenance of histone acetylation by HDAC inhibitors, such as trichostatin A (TSA), has been examined for the reduction of polyQ toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…1 It is hypothesized that polyQ aggregation suppresses neuronal transcriptional activity by sequestering histone acetyltransferases (HAT) from chromosomes and thus polyQ causes neuronal cell death. [2][3][4] Bax is a proapoptotic member of Bcl-2 family proteins that plays a key role in programmed cell death in neurons. 5,6 Recently, mutant huntingtin with expanded polyQ was shown to activate p53 and increase the expression level of Bax.…”

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confidence: 99%

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Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation

Yokota

Gama

et al. 2007

Cell Death Differ

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Polyglutamine (polyQ) diseases, such as Huntington's disease and Machado-Joseph disease (MJD), are caused by gain of toxic function of abnormally expanded polyQ tracts. Here, we show that expanded polyQ of ataxin-3 (Q79C), a gene that causes MJD, stimulates Ku70 acetylation, which in turn dissociates the proapoptotic protein Bax from Ku70, thereby promoting Bax activation and subsequent cell death. The Q79C-induced cell death was significantly blocked by Ku70 or Bax-inhibiting peptides (BIPs) designed from Ku70. Furthermore, expression of SIRT1 deacetylase and the addition of a SIRT1 agonist, resveratrol, reduced Q79C toxicity. In contrast, mimicking acetylation of Ku70 abolished the ability of Ku70 to suppress Q79C toxicity. These results indicate that Bax and Ku70 acetylation play important roles in Q79C-induced cell death, and that BIP may be useful in the development of therapeutics for polyQ diseases. Nine inherited neurodegenerative disorders with expanded polyglutamine (polyQ) are caused by mutations in different genes, but they likely share the common pathology in which expanded polyQ gains toxic functions. 1 The molecular mechanism of neuronal toxicity of polyQ remains enigmatic. Recent findings suggest that the intracellular aggregation of polyQ causes cellular stress responses that trigger neuronal cell death. 1 It is hypothesized that polyQ aggregation suppresses neuronal transcriptional activity by sequestering histone acetyltransferases (HAT) from chromosomes and thus polyQ causes neuronal cell death. [2][3][4] Bax is a proapoptotic member of Bcl-2 family proteins that plays a key role in programmed cell death in neurons. 5,6 Recently, mutant huntingtin with expanded polyQ was shown to activate p53 and increase the expression level of Bax. 7 Based on these previous findings, we became interested in examining the role of Bax in polyQ-induced cell death. Recently, we developed a series of cytoprotective membrane-permeable pentapeptides that rescue cells from Baxmediated cell death. These peptides are named Bax-inhibiting peptides (BIPs) and were designed from the Bax binding domain of Ku70. [8][9][10] Ku70 is a multifunctional protein playing roles in DNA repair and cell survival. 11 Ku70 has been shown to inhibit Bax-mediated cell death by binding Bax in the cytosol. 12-14 The present study demonstrates that BIP can rescue cells from polyQ toxicity, and that polyQ promotes Bax-mediated cell death by inducing Ku70 acetylation that activates Bax. ResultsBIP suppresses Q79C-induced cell death. BIPs consisting of five amino acids (e.g. VPMLK and VPTLK) were used in this study. A mutated peptide (i.e. IPMIK) that does not bind Bax but retains cell permeability was also used in this study as a negative control (NC). For the investigation of polyQ toxicity, we used the C-terminal, truncated fragment of the Machado-Joseph disease 1 (MJD1) gene product, ataxin-3, which includes an expanded polyQ stretch (79 glutamine repeats, Q79C). 15,16 As a negative control, ataxin-3 C-terminus with 22 or 35 glutamine rep...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation

Yokota

Gama

et al. 2007

Cell Death Differ

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“…Several reports have shown that expanded polyglutamine expression decreases the acetylation of core histones such as H3 and H4 (12,13,17,19). We first confirmed this observation in our cell culture model of polyglutamine disease (40).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed polyglutamine expansions have been identified in aggregated proteins in nine inherited neurodegenerative disorders, including HD and MJD (also called SCA3), ␣-synuclein in PD, DLB, and multisystem atrophy, and TDP-43 in certain types of front-temporal dementia, PD without Lewy bodies, and ALS (4 -6). These proteins accumulate in the cytoplasm, the nucleus, or both, and have been proposed to trigger multiple cellular responses, such as cell death, proteasomal dysfunction, ER stress, and oxidative stress (7)(8)(9)(10)(11), as well as transcriptional dysregulation (12,13).…”

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Valosin-containing Protein (VCP) in Novel Feedback Machinery between Abnormal Protein Accumulation and Transcriptional Suppression

Koike

Fukushi

Ichinohe

et al. 2010

Journal of Biological Chemistry

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Abnormal protein accumulation is often observed in human neurodegenerative disorders such as polyglutamine diseases and Parkinson disease. Genetic and biochemical analyses indicate that valosin-containing protein (VCP) is a crucial molecule in the pathogenesis of human neurodegenerative disorders. We report here that VCP was specifically modified in neuronal cells with abnormal protein accumulation; this modification caused the translocation of VCP into the nucleus. Modification-mimic forms of VCP induced transcriptional suppression with deacetylation of core histones, leading to cell atrophy and the decrease of de novo protein synthesis. Preventing VCP nuclear translocation in polyglutamine-expressing neuronal cells and Drosophila eyes mitigated neurite retraction and eye degenerations, respectively, concomitant with the recovery of core histone acetylation. This represents a novel feedback mechanism that regulates abnormal protein levels in the cytoplasm during physiological processes, as well as in pathological conditions such as abnormal protein accumulation in neurodegenerations.

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Neurogenetics in the Postgenomic Era

Tsuji¹

2001

Arch Neurol

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Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription

Cited by 379 publications

References 48 publications

Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation

Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation

Valosin-containing Protein (VCP) in Novel Feedback Machinery between Abnormal Protein Accumulation and Transcriptional Suppression

Neurogenetics in the Postgenomic Era

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