S6K1 is a multifaceted regulator of Mdm2 that connects nutrient status and DNA damage response

Lai, Keng Po; Leong, Wai Fook; Chau, Jenny Fung Ling; Jia, Dongyu; Zeng, Li; Liu, Huijuan; He, Lin; Hao, Aijun; Zhang, Hongbing; Meek, David W.; Velagapudi, Chakradhar; Habib, Samy L.; Li, Baojie

doi:10.1038/emboj.2010.166

Cited by 107 publications

(97 citation statements)

References 44 publications

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“…Another major regulator of mitochondrial homeostasis and senescence is the protein kinase mTOR, which has been demonstrated to regulate p53 accumulation through MDM2‐dependent or independent mechanisms (Lai et al, 2010). In cells stimulated with Tyr, mTOR was persistently activated, as shown by the phosphorylation level of its major target p70S6K, which was prevented by treatment with the mTOR inhibitor rapamycin (Figure 5f) or by siRNA‐mediated silencing of MAO‐A (Figure 5g).…”

Section: Resultsmentioning

confidence: 99%

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

et al. 2018

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Cellular senescence, the irreversible cell cycle arrest observed in somatic cells, is an important driver of age‐associated diseases. Mitochondria have been implicated in the process of senescence, primarily because they are both sources and targets of reactive oxygen species (ROS). In the heart, oxidative stress contributes to pathological cardiac ageing, but the mechanisms underlying ROS production are still not completely understood. The mitochondrial enzyme monoamine oxidase‐A (MAO‐A) is a relevant source of ROS in the heart through the formation of H2O2 derived from the degradation of its main substrates, norepinephrine (NE) and serotonin. However, the potential link between MAO‐A and senescence has not been previously investigated. Using cardiomyoblasts and primary cardiomyocytes, we demonstrate that chronic MAO‐A activation mediated by synthetic (tyramine) and physiological (NE) substrates induces ROS‐dependent DNA damage response, activation of cyclin‐dependent kinase inhibitors p21cip, p16ink4a, and p15ink4b and typical features of senescence such as cell flattening and SA‐β‐gal activity. Moreover, we observe that ROS produced by MAO‐A lead to the accumulation of p53 in the cytosol where it inhibits parkin, an important regulator of mitophagy, resulting in mitochondrial dysfunction. Additionally, we show that the mTOR kinase contributes to mitophagy dysfunction by enhancing p53 cytoplasmic accumulation. Importantly, restoration of mitophagy, either by overexpression of parkin or inhibition of mTOR, prevents mitochondrial dysfunction and induction of senescence. Altogether, our data demonstrate a novel link between MAO‐A and senescence in cardiomyocytes and provides mechanistic insights into the potential role of MAO‐dependent oxidative stress in age‐related pathologies.

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Section: Resultsmentioning

confidence: 99%

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

et al. 2018

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“…Another protein with markedly reduced phosphorylation in MKN45 is the proline-rich AKT substrate of 40-kDa (PRAS40) which inhibits the activity of the mTOR complex 1 (mTORC1) kinase. Phosphorylation of PRAS40 by Akt and by mTORC1 itself results in activation of mTORC1 activity and enhancement of cell survival and growth via activation of p-70S6K and 4-EBP1 [43][44][45]. Accordingly, phosphorylation of 70S6K und Akt is downregulated in MKN45 cells in response to ganetespib.…”

Section: Mkn1mentioning

confidence: 87%

2208 In vitro cytotoxic activities of the oral platinum(IV) prodrug oxoplatin and HSP90 inhibitor ganetespib against a panel of gastric cancer cell lines

Klameth¹,

Rath²,

Kriwanek³

et al. 2015

European Journal of Cancer

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“…56 Binding of S6K1 directly to MDM2 may also play a role in p53 control. 22 Thus, a number of different mechanisms triggered by rapamycin treatment may converge and blunt the p53 pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Another potential mechanism whereby rapamycin blunts p53 may involve the p38MAPK-AKT-mTOR-S6K1 signaling network that is activated in response to genotoxic stress. 22 Phosphorylated and active S6K1 binds, and phosphorylates MDM2 and inhibits its E3 ligase activity thereby stabilizing p53. We therefore investigated the role of S6K1 as a possible mediator of p53 stabilization upon nucleolar stress.…”

Section: Increased Mdm2 Levels In Rapamycin Treated Cellsmentioning

confidence: 99%

“…21 For example, the mTOR-S6K1 pathway is activated in response to genotoxic stress and in turn S6K1 binds and inhibits MDM2. 22 On the other hand, p53 transcriptionally induces a number of genes involved in suppression of the mTOR pathway including Sestrin1/2 and TSC2. 23 Moreover, inhibition of mTOR may engage the Akt kinase through a feedback mechanism to phosphorylate MDM2 causing stabilization of MDM2 and subsequent reduction of p53.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

mTOR inhibitors blunt the p53 response to nucleolar stress by regulating RPL11 and MDM2 levels

Goudarzi¹,

Nistér

Lindström³

2014

Cancer Biology & Therapy

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target of rapamycin; MTT, (3-[4, 5-dimethylthiazol-2-yl]-2, 5 diphenyl tetrazolium bromide); PI, propidium iodide Mechanistic target of rapamycin (mTOR) is a master regulator of cell growth through its ability to stimulate ribosome biogenesis and mRNA translation. In contrast, the p53 tumor suppressor negatively controls cell growth and is activated by a wide range of insults to the cell. The mTOR and p53 signaling pathways are connected by a number of different mechanisms. Chemotherapeutics that inhibit ribosome biogenesis often induce nucleolar stress and activation of p53. Here we have investigated how the p53 response to nucleolar stress is affected by simultaneous mTOR inhibition in osteosarcoma and glioma cell lines. We found that inhibitors of the mTOR pathway including rapamycin, wortmannin, and caffeine blunted the p53 response to nucleolar stress induced by actinomycin D. Synthetic inhibitors of mTOR (temsirolimus, LY294.002 and PP242) also impaired actinomycin D triggered p53 stabilization and induction of p21. Ribosomal protein (RPL11) is known to be required for p53 protein stabilization following nucleolar stress. Treatment of cells with mTOR inhibitors may lead to reduced synthesis of RPL11 and thereby destabilize p53. We found that rapamycin mimicked the effect of RPL11 depletion in terms of blunting the p53 response to nucleolar stress. However, the extent to which the levels of p53 and RPL11 were reduced by rapamycin varied between cell lines. Additional mechanisms whereby rapamycin blunts the p53 response to nucleolar stress are likely to be involved. Indeed, rapamycin increased the levels of endogenous MDM2 despite inhibition of its phosphorylation at Ser-166. Our findings may have implications for the design of combinatorial cancer treatments with mTOR pathway inhibitors.

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S6K1 is a multifaceted regulator of Mdm2 that connects nutrient status and DNA damage response

Cited by 107 publications

References 44 publications

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

2208 In vitro cytotoxic activities of the oral platinum(IV) prodrug oxoplatin and HSP90 inhibitor ganetespib against a panel of gastric cancer cell lines

mTOR inhibitors blunt the p53 response to nucleolar stress by regulating RPL11 and MDM2 levels

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