Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation

Strom, Evguenia; Sathe, Swati S.; Komarov, Pavel G.; Chernova, Olga B.; Pavlovska, Ivanda; Shyshynova, Inna; Bosykh, Dmitriy A.; Burdelya, Lyudmila; Macklis, Roger M.; Skaliter, Rami; Komarova, Elena A.; Gudkov, Andrei V.

doi:10.1038/nchembio809

Cited by 302 publications

(274 citation statements)

References 28 publications

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“…S3). We then utilized pifithrin-, a recently reported small molecule that specifically inhibits p53 binding to the mitochondria (36), to further test the role of the mitochondria associated p53 in hESCs. We found that pifithrin-significantly increased the survival rate of H1 cells after UV irradiation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulation of Apoptosis and Differentiation by p53 in Human Embryonic Stem Cells

Han

Qing

et al. 2007

Journal of Biological Chemistry

229

230

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The essentially infinite expansion potential and pluripotency of human embryonic stem cells (hESCs) makes them attractive for cell-based therapeutics. In contrast to mouse embryonic stem cells (mESCs), hESCs normally undergo high rates of spontaneous apoptosis and differentiation, making them difficult to maintain in culture. Here we demonstrate that p53 protein accumulates in apoptotic hESCs induced by agents that damage DNA. However, despite the accumulation of p53, it nevertheless fails to activate the transcription of its target genes. This inability of p53 to activate its target genes has not been observed in other cell types, including mESCs. We further demonstrate that p53 induces apoptosis of hESCs through a mitochondrial pathway. Reducing p53 expression in hESCs in turn reduces both DNA damage-induced apoptosis as well as spontaneous apoptosis. Reducing p53 expression also reduces spontaneous differentiation and slows the differentiation rate of hESCs. Our studies reveal the important roles of p53 as a critical mediator of human embryonic stem cells survival and differentiation.Human embryonic stem cells (hESCs) 3 are capable of essentially unlimited self-renewal and retain the developmental potential to differentiate into almost any cell type. These characteristics of hESCs make them attractive for tissue and cellbased therapies (1, 2). Previously, basic fibroblast growth factor and activin A were identified as self-renewal factors (3-6). However, for reasons that are not clear, hESCs often display high rates of spontaneous apoptosis and differentiation in culture, thus making the process of expanding these cells highly inefficient (3, 7-10). For example, Dravid et al. (8) reported that, under routine culture conditions, Ͼ30% of hESCs undergo spontaneous apoptosis. Furthermore, Ezashi et al. (12) showed that nearly 40% of hESCs undergo spontaneous differentiation after 12 days of culture in normoxic conditions. Finally, Maitra et al. (13) reported that multiple passages of hESCs can cause genomic alterations, which may limit the therapeutic application of hESCs. In contrast to hESCs, mouse embryonic stem cells (mESCs) undergo lower rates of spontaneous apoptosis and differentiation (14). Moreover, they maintain their pluripotency and genomic stability longer than hESCs (15). The reason for these different species-specific phenotypes in embryonic stem cells is currently unknown.The p53 tumor suppressor gene is a strong candidate for playing a role in the observed phenotypes of hESCs, because it regulates various cellular processes, including apoptosis, differentiation, and genomic integrity (16). In many cell types p53 plays a crucial role in controlling apoptosis and cell cycle arrest when these cells are exposed to stress-inducing conditions (17). In response to stress, p53 accumulates and transactivates downstream target genes such as mdm2 (responsible for the feedback degradation circuitry of p53), p21 (responsible for cell cycle control), bax, noxa, and puma (responsible for DNA damage-induced ...

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Section: Resultsmentioning

confidence: 99%

Regulation of Apoptosis and Differentiation by p53 in Human Embryonic Stem Cells

Han

Qing

et al. 2007

Journal of Biological Chemistry

229

230

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“…This effect may be due to inhibition by Ptx of IR-induced p53 activation. It was shown that p53 inhibitors caused radioprotective effect in mice [34].…”

Section: Discussionmentioning

confidence: 99%

Biochemical effects of combined action of ?-irradiation and paclitaxel on anaplastic thyroid cancer cells

Пушкарев

Ковзун²,

Пушкарев³

et al. 2013

Ukr.Biochem.J.

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“…We used the following compounds to modulate aminoglycoside-induced hair cell death: the Bax channel blocker (±)-1-(3,6-dibromocarbazol-9-yl)-3-piperazin-1-yl-propan-2-ol, bis TFA (Bombrun et al 2003), the p53 inhibitors pifithrin-α (PFTα) (Komarov et al 1999;Endo et al 2006) and pifithrin-μ (PFTμ) (Strom et al 2006), and the Mdm2 inhibitor nutlin-3a (Vassilev et al 2004). All inhibitors were purchased from EMD Millipore (Darmstadt, Germany) and dissolved in DMSO.…”

Section: Drug Treatmentsmentioning

confidence: 99%

“…Aminoglycosides are reported to induce changes in mitochondrial morphology and function in hair cells, suggesting a central importance for mitochondria in hair cell death signaling (Owens et al 2007;Jensen-Smith et al 2012). We therefore examined the necessity for mitochondrial p53 activity using the specific inhibitor PFTμ (Strom et al 2006); 25 μM PFTμ provided statistically significant but modest protection from acute neomycin or acute gentamicin exposure (Fig. 3), with the magnitude of protection virtually identical to that seen with PFTα.…”

Section: P53 Inhibition Protects Hair Cells From Neomycinor Gentamicimentioning

confidence: 99%

“…PFTμ is hypothesized to inhibit p53 mitochondrial activity by disrupting binding of p53 to Bcl2 or Bcl-xL, which then allows them to bind and inhibit Bax and thereby promote cell survival (Strom et al 2006;Morita et al 2010). We therefore asked if overexpressing Bcl2 would protect hair cells from aminoglycoside damage.…”

Section: Bcl2 Overexpression Protects Hair Cells From Gentamicin Toximentioning

confidence: 99%

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Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

Coffin

Rubel

Raible

2013

JARO

112

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Sensorineural hearing loss is a normal consequence of aging and results from a variety of extrinsic challenges such as excessive noise exposure and certain therapeutic drugs, including the aminoglycoside antibiotics. The proximal cause of hearing loss is often death of inner ear hair cells. The signaling pathways necessary for hair cell death are not fully understood and may be specific for each type of insult. In the lateral line, the closely related aminoglycoside antibiotics neomycin and gentamicin appear to kill hair cells by activating a partially overlapping suite of cell death pathways. The lateral line is a system of hair cell-containing sense organs found on the head and body of aquatic vertebrates. In the present study, we use a combination of pharmacologic and genetic manipulations to assess the contributions of p53, Bax, and Bcl2 in the death of zebrafish lateral line hair cells. Bax inhibition significantly protects hair cells from neomycin but not from gentamicin toxicity. Conversely, transgenic overexpression of Bcl2 attenuates hair cell death due to gentamicin but not neomycin, suggesting a complex interplay of pro-death and pro-survival proteins in drug-treated hair cells. p53 inhibition protects hair cells from damage due to either aminoglycoside, with more robust protection seen against gentamicin. Further experiments evaluating p53 suggest that inhibition of mitochondrial-specific p53 activity confers significant hair cell protection from either aminoglycoside. These results suggest a role for mitochondrial p53 activity in promoting hair cell death due to aminoglycosides, likely upstream of Bax and Bcl2.

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Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation

Cited by 302 publications

References 28 publications

Regulation of Apoptosis and Differentiation by p53 in Human Embryonic Stem Cells

Regulation of Apoptosis and Differentiation by p53 in Human Embryonic Stem Cells

Biochemical effects of combined action of ?-irradiation and paclitaxel on anaplastic thyroid cancer cells

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

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