Transcription-independent pro-apoptotic functions of p53

Moll, Ute M.; Wolff, Sonja; Speidel, Daniel; Deppert, Wolfgang

doi:10.1016/j.ceb.2005.09.007

Cited by 425 publications

(360 citation statements)

References 39 publications

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“…Since their initial finding of mitochondrial p53 in 2000 (Marchenko et al ., 2000), Moll and colleagues have performed pioneering studies, showing that p53 is specifically targeted to mitochondria and plays transcription‐independent pro‐apoptotic functions (Mihara et al ., 2003; Erster & Moll, 2004; Moll et al ., 2005). p53 directly interacts with multidomain proteins of the Bcl‐2 family at the mitochondrial outer membrane and induces mitochondrial outer membrane permeabilization, which is a prominent apoptotic checkpoint (Mihara et al ., 2003; Tomita et al ., 2006; Follis et al ., 2014).…”

Section: Discussionmentioning

confidence: 99%

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

et al. 2017

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SummaryAlzheimer's disease (AD) is the leading cause of dementia in the elderly. Despite decades of study, effective treatments for AD are lacking. Mitochondrial dysfunction has been closely linked to the pathogenesis of AD, but the relationship between mitochondrial pathology and neuronal damage is poorly understood. Sirtuins (SIRT, silent mating type information regulation 2 homolog in yeast) are NAD‐dependent histone deacetylases involved in aging and longevity. The objective of this study was to investigate the relationship between SIRT3 and mitochondrial function and neuronal activity in AD. SIRT3 mRNA and protein levels were significantly decreased in AD cerebral cortex, and Ac‐p53 K320 was significantly increased in AD mitochondria. SIRT3 prevented p53‐induced mitochondrial dysfunction and neuronal damage in a deacetylase activity‐dependent manner. Notably, mitochondrially targeted p53 (mito‐p53) directly reduced mitochondria DNA‐encoded ND2 and ND4 gene expression resulting in increased reactive oxygen species (ROS) and reduced mitochondrial oxygen consumption. ND2 and ND4 gene expressions were significantly decreased in patients with AD. p53‐ChIP analysis verified the presence of p53‐binding elements in the human mitochondrial genome and increased p53 occupancy of mitochondrial DNA in AD. SIRT3 overexpression restored the expression of ND2 and ND4 and improved mitochondrial oxygen consumption by repressing mito‐p53 activity. Our results indicate that SIRT3 dysfunction leads to p53‐mediated mitochondrial and neuronal damage in AD. Therapeutic modulation of SIRT3 activity may ameliorate mitochondrial pathology and neurodegeneration in AD.

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Section: Discussionmentioning

confidence: 99%

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

et al. 2017

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“…The observation that sequestration of p53 into a cytoplasmic inclusion body blocks the import of p53 into mitochondria suggests that substitutions C454S/C456S may interfere with the ability of the Ad5 protein to antagonize proapoptotic activities of p53, operating within the mitochondrial pathway of apoptosis. Considerable evidence suggests that this antiproliferative activity of p53 is largely mediated through transcription-independent functions (for review, see Moll et al, 2005). Such a mechanism would fit well with our result that E1B-C454S/C456S is defective in focal transformation, but blocks p53-stimulated transcription (Table 2 in Supplementary data; Figure 3), and the finding that none of the few foci induced by pm490/1/5A could be established into permanent cell lines (Table 2 in Supplementary data), because this mutant is defective in both inhibition of p53-stimulated transcription (Teodoro et al, 1994;Teodoro and Branton, 1997, and Table 2 in Supplementary data) and formation of the cytoplasmic inclusion body .…”

Section: Discussionmentioning

confidence: 99%

Adenovirus type 5 early region 1B 55-kDa oncoprotein can promote cell transformation by a mechanism independent from blocking p53-activated transcription

Härtl

Zeller²,

Blanchette

et al. 2008

Oncogene

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Inhibition of p53-activated transcription is an integral part of the mechanism by which early region 1B 55K oncoprotein (E1B-55K) from adenovirus type 5 (Ad5) contributes to complete cell transformation in combination with Ad E1A. In addition, more recent data suggest that the mode of action of the Ad protein during transformation may involve additional functions and other protein interactions. In the present study, we performed a comprehensive mutational analysis to assign further transforming functions of Ad5 E1B-55K to distinct domains within the viral polypeptide. Results from these studies show that the functions required for transformation are encoded within several patches of the 55K primary sequence, including several clustered cysteine and histidine residues, some of which match the consensus for zinc fingers. In addition, two amino-acid substitutions (C454S/C456S) created a 55K mutant protein, which had substantially reduced transforming activity. Interestingly, the same mutations neither affected binding to p53 nor inhibition of p53-mediated transactivation. Therefore, an activity necessary for efficient transformation of primary rat cells can be separated from functions required for inhibition of p53-stimulated transcription. Our data indicate that this activity is linked to the ability of the Ad5 protein to bind to components of the Mre11/Rad50/NBS1 DNA doublestrand break repair complex, and/or its ability to assemble multiprotein aggregates in the cytoplasm and nucleus of transformed rat cells. These results introduce a new function for Ad5 E1B-55K and suggest that the viral protein contributes to cell transformation through p53 transcription-dependent and -independent pathways.

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“…p53 can transcriptionally regulate Bax, and p53 can also interact directly with Bax protein and other Bcl2 family members in the cytosol or mitochondria (Mihara et al 2003;Moll et al 2005;Chipuk and Green 2006). In a previous screen of a hair cells from neomycin damage using either acute (C) or continuous (E) exposure paradigms.…”

Section: P53 Inhibition Protects Hair Cells From Neomycinor Gentamicimentioning

confidence: 99%

“…Importantly, the slow form of Bax-independent death induced by DNA damage involved p53 activity (Besirli et al 2003). p53 can also interact directly with pro-survival and pro-cell death Blc2 family members to activate mitochondrial-associated cell death path-ways (Mihara et al 2003;Chipuk et al 2004;Moll et al 2005;Han et al 2010). Protein binding and colocalization experiments are necessary to further dissect the relative contributions of these proteins to aminoglycoside ototoxicity.…”

Section: Bcl2 Proteins and Aminoglycoside Ototoxicitymentioning

confidence: 99%

“…Bcl2 family members have been linked to aminoglycoside ototoxicity in rodent models and noise-induced hearing loss (Cunningham et al 2004;Vicente-Torres and Schacht 2006;Yamashita et al 2008;Pfannenstiel et al 2009). p53 is best recognized as a transcription factor with hundreds of downstream targets, playing a central role in DNA repair, cell cycle regulation, and cell death (reviewed in Pietsch et al 2008;Levine and Oren 2009). However, transcription-independent p53 activity is also important in many cell death processes by its association with cytoplasmic or mitochondrial proteins, including members of the Bcl2 family (Moll et al 2005;Chipuk and Green 2006;Green and Kroemer 2009). p53 is implicated in cisplatin ototoxicity (Zhang et al 2003), but a potential role in aminoglycoside-induced hair cell death has not been explored.…”

Section: Introductionmentioning

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

102

116

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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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Transcription-independent pro-apoptotic functions of p53

Cited by 425 publications

References 39 publications

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease

Adenovirus type 5 early region 1B 55-kDa oncoprotein can promote cell transformation by a mechanism independent from blocking p53-activated transcription

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

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