p53 Mediates Cellular Dysfunction and Behavioral Abnormalities in Huntington’s Disease

Bae, Byoung-Il; Xu, Hong; Igarashi, Shuichi; Fujimuro, Masahiro; Agrawal, Nishant; Taya, Yoichi; Hayward, S. Diane; Moran, Timothy H.; Montell, Craig; Ross, Christopher A.; Snyder, Solomon H.; Sawa, Akira

doi:10.1016/j.neuron.2005.06.005

Cited by 440 publications

(422 citation statements)

References 71 publications

(1 reference statement)

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“…A 30 % increase in Hdac1 expression was also observed in the cortices and striata of HD R6/2 mice, but is unlikely to be a cause of a detectable decrease in global histone acetylation [89]. Alterations in the acetylation of CBP-target nonhistone proteins, such as p53 [9,90,91] or the upstream binding factor-1 [92] also play a role in the progression of the disease. The Htt protein is subjected to acetylation that targets mutant Htt to autophagosomes for degradation [91].…”

Section: Hat Impairment In Neurodegenerative Disordersmentioning

confidence: 95%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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Section: Hat Impairment In Neurodegenerative Disordersmentioning

confidence: 95%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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“…Interestingly, the ability of mutp53 proteins to bind non-canonic DNA structures formed by (CTG CAG) tracts is not unique to mutp53, but derives from the inherent DNA structure-dependent binding (DSDB) activity of wtp53 (Go¨hler et al, 2002;Walter et al, 2005). Considering that out the formation of hairpin and slipped DNA structures is the underlying mechanism of (CTG CAG) tract instability associated with several neurodegenerative diseases (Sinden et al, 2002), the finding that wtp53 and mutp53 proteins target (CTG CAG) tracts in a DSSB mode may provide important insights into the emerging connection between wtp53 and neurodegenerative diseases (Bae et al, 2005;Feng et al, 2006). Whereas an involvement of mutp53 in the pathophysiology of neurodegenerative diseases seems to be rather unlikely, a more intriguing possibility is that the binding of (CTG CAG) tracts by mutp53 proteins could be relevant for establishing specific patterns of chromatin structure in cancer cells.…”

Section: Direct Binding Of Mutp53 To Dnamentioning

confidence: 99%

Interactions of mutant p53 with DNA: guilt by association

Kim

Deppert

2007

Oncogene

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Since the very early days of p53 research, the gain of oncogenic activities by some mutant p53 proteins had been suspected as an important factor contributing to cancer progression. Considerable progress towards understanding the biology of mutant p53 has been made during the last years, the quintessence being the realization that the impact of mutant p53 proteins on the transcriptome of a tumor cell is much more global than previously thought. The emerging role of mutant p53 proteins in coordinating oncogenic signaling and chromatin modifying activities reveals an until now unsuspected function of these proteins as important modifiers of the oncogenic transcriptional response. Notwithstanding the fact that the sequencespecific DNA binding activity of mutant p53 proteins is impaired, they are still able to associate with specific loci on DNA by utilizing different mechanisms. The ability to associate with DNA appears to be crucial for the master role of mutant p53 proteins in coordinating oncogenic transcriptional responses.

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“…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.…”

mentioning

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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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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p53 Mediates Cellular Dysfunction and Behavioral Abnormalities in Huntington’s Disease

Cited by 440 publications

References 71 publications

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

Interactions of mutant p53 with DNA: guilt by association

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

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