Bax-inhibiting peptides derived from Ku70 and cell-penetrating pentapeptides

Gómez, José Antonio Caride; Gama, Vivian; Yoshida, Tomoyuki; Sun, Weizhong; Hayes, Paulette L.; Leskov, Konstantin; Boothman, D.; Matsuyama, Shigemi

doi:10.1042/bst0350797

Cited by 90 publications

(127 citation statements)

References 40 publications

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“…To identify the specific apoptotic pathways induced by hypoxia in cells over-expressing Tid1, several different apoptotic inhibitors, including BAX-inhibitor peptide, caspase-9 inhibitor (Z-LEHD-FMK) and caspase-8 inhibitor (Z-IETD-FMK) were used (Gomez et al, 2007) (Figure 4a). BAX-inhibitor peptide is designed based on the Bax-binding domain of Ku70 and this interaction suppresses Bax-mediated apoptosis (Gomez et al, 2007). BAX-inhibitor peptide alone was sufficient to reduce levels of apoptosis (Figure 4b) and inhibit cytochrome c release (Figure 4c) induced by hypoxic stress with DFX treatment whether or not Tid1 was over-expressed.…”

Section: Resultsmentioning

confidence: 99%

Tid1 is a new regulator of p53 mitochondrial translocation and apoptosis in cancer

et al. 2009

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The p53 tumor suppressor protein induces apoptosis in response to genotoxic and environmental stresses. Recent studies have revealed the existence of a transcriptionindependent mitochondrial p53 apoptotic pathway; however, the mechanism that regulates its translocation to the mitochondria has been unknown. In this study, we show that the tumor suppressor Tid1 forms a complex with p53 under hypoxic conditions that directs p53 translocation to the mitochondria and the subsequent initiation of the mitochondrial apoptosis pathway. Loss of Tid1 expression abrogated p53 translocation to the mitochondria and inhibited apoptosis, whereas the over-expression of Tid1 promoted p53 mitochondrial localization and apoptosis. Tid1's mitochondrial signal sequence and DnaJ domain were both required for the movement of the p53-Tid1 complex from the cytosol to the mitochondria. When Tid is over-expressed in cancer cell lines expressing mutant p53 isoforms defective in transcriptional activity, mitochondrial localization and pro-apoptotic activities of the mutant p53 proteins was restored. Our results establish Tid1 as a novel regulator of p53-mediated apoptosis, and suggest that therapies designed to enhance Tid1's function in promoting mitochondrial localization of p53 and apoptosis could be an effective therapy in many cancers.

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Section: Resultsmentioning

confidence: 99%

Tid1 is a new regulator of p53 mitochondrial translocation and apoptosis in cancer

et al. 2009

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“…Because BIP is designed from Ku70 which prevents Bax-mediated cell death, [8][9][10] we examined whether Q79C had any influence on the binding between Ku70 and Bax. Q79C significantly decreased the interaction between Bax and Ku70 (Figure 4a and b).…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

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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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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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“…A role in modulating the DNA damage sensors ATM and ATR has also recently been reported [5]. While the previous functions are largely nuclear, Ku70 has a specific activity in the cytoplasm favoring cell survival by binding and sequestering the pro-apoptosis protein Bax [6]. Finally, for reasons that are still not clear, Ku70 and Ku80 are antigenic targets of the immune system in people suffering from certain autoimmune diseases.…”

Section: Introductionmentioning

confidence: 93%

Ku70 is stabilized by increased cellular SUMO

Yurchenko

Xue

Gama

et al. 2008

Biochemical and Biophysical Research Communications

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Ku70 is a protein that finds itself at the heart of several important cellular processes. It is essential to the Non-Homologous End Joining pathway as a part of the DNA-end binding complex, required for proper maintenance of telomeres and contributes to the DNA damage recognition and regulation of apoptosis. Forces that regulate Ku70 are therefore likely to have large consequences on the physiologic state of the cell. We report here that transient expression of the small protein SUMO resulted in a surprising increase in the abundance of Ku70. Surprisingly, the direct SUMOylation of Ku70 does not appear to be required for this effect. Rather, Ku70 appears to be stabilized through indirect effects on the rate of degradation. The same outcome was obtained by raising the expression of enzymes that promote SUMOylation. It is likely that many other proteins will be similarly regulated, providing a general control of cellular state.

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Bax-inhibiting peptides derived from Ku70 and cell-penetrating pentapeptides

Cited by 90 publications

References 40 publications

Tid1 is a new regulator of p53 mitochondrial translocation and apoptosis in cancer

Tid1 is a new regulator of p53 mitochondrial translocation and apoptosis in cancer

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

Ku70 is stabilized by increased cellular SUMO

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