The essence of senescence: Figure 1.

Kuilman, Thomas; Michaloglou, Chrysiis; Mooi, Wolter J.; Peeper, Daniel S.

doi:10.1101/gad.1971610

Cited by 1,748 publications

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“…Cellular senescence is a highly stable cell cycle arrest triggered by replicative exhaustion or in response to different stresses (Collado et al ., 2007; Kuilman et al ., 2010). Senescence was first described in vitro , but its relevance as a physiological process in vivo is increasingly clear.…”

Section: Introductionmentioning

confidence: 99%

“…Senescence was first described in vitro , but its relevance as a physiological process in vivo is increasingly clear. Senescence induced in response to oncogenes has been recognized as a tumour suppressor mechanism (Kuilman et al ., 2010; Perez‐Mancera et al ., 2014). In addition, senescence also has roles in early embryogenesis and aging amongst other physiological processes (Munoz‐Espin & Serrano, 2014).…”

Section: Introductionmentioning

confidence: 99%

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CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

et al. 2015

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SummaryPolycomb repressive complexes (PRC1 and PRC2) are epigenetic regulators that act in coordination to influence multiple cellular processes including pluripotency, differentiation, cancer and senescence. The role of PRCs in senescence can be mostly explained by their ability to repress the INK4/ARF locus. CBX7 is one of five mammalian orthologues of Drosophila Polycomb that forms part of PRC1. Despite the relevance of CBX7 for regulating senescence and pluripotency, we have a limited understanding of how the expression of CBX7 is regulated. Here we report that the miR‐9 family of microRNAs (miRNAS) downregulates the expression of CBX7. In turn, CBX7 represses miR‐9‐1 and miR‐9‐2 as part of a regulatory negative feedback loop. The miR‐9/CBX7 feedback loop is a regulatory module contributing to induction of the cyclin‐dependent kinase inhibitor (CDKI) p16INK 4a during senescence. The ability of the miR‐9 family to regulate senescence could have implications for understanding the role of miR‐9 in cancer and aging.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

et al. 2015

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“…For the senescence‐dependent proliferation assay, we prepared wild‐type (WT) and TXNIP ‐/‐ (KO) MEF cells, which undergo senescence after a limited number of passages in culture (Kuilman, Michaloglou, Mooi, & Peeper, 2010). WT and KO MEF cells were cultured by subculturing 2 × 10 5 cells at 3‐day intervals to investigate the function of TXNIP on replicative senescence (Dimri et al, 1995), with the cell number counted at the same intervals.…”

Section: Resultsmentioning

confidence: 99%

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

et al. 2018

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Aging is associated with an inevitable and universal loss of cell homeostasis and restricts an organism's lifespan by an increased susceptibility to diseases and tissue degeneration. The glucose uptake associated with producing energy for cell survival is one of the major causes of ROS production under physiological conditions. However, the overall mechanisms by which glucose uptake results in cellular senescence remain mysterious. In this study, we found that TXNIP deficiency accelerated the senescent phenotypes of MEF cells under high glucose condition. TXNIP‐/‐ MEF cells showed greater induced glucose uptake and ROS levels than wild‐type cells, and N‐acetylcysteine (NAC) treatment rescued the cellular senescence of TXNIP‐/‐ MEF cells. Interestingly, TXNIP‐/‐ MEF cells showed continuous activation of AKT during long‐term subculture, and AKT signaling inhibition completely blocked the cellular senescence of TXNIP‐/‐ MEF cells. In addition, we found that TXNIP interacted with AKT via the PH domain of AKT, and their interaction was increased by high glucose or H2O2 treatment. The inhibition of AKT activity by TXNIP was confirmed using western blotting and an in vitro kinase assay. TXNIP deficiency in type 1 diabetes mice (Akita) efficiently decreased the blood glucose levels and finally increased mouse survival. However, in normal mice, TXNIP deficiency induced metabolic aging of mice and cellular senescence of kidney cells by inducing AKT activity and aging‐associated gene expression. Altogether, these results suggest that TXNIP regulates cellular senescence by inhibiting AKT pathways via a direct interaction under conditions of glucose‐derived metabolic stress.

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“…As long as cell cycle checkpoint function is maintained, epithelial cells exit the cell cycle into cellular senescence as hallmarked by upregulation of cyclin-dependent kinase inhibitors, such as p16, p21, and p27, and expression of senescence-associated β-galactosidase. 13 If cell cycle checkpoint function is impaired, persisting DNA damage will be transferred into the next round of mitosis leading to aberrant chromosomal segregation. Upon 2–3 rounds of anomalous mitosis, highly aneuploid cells with huge and/or multiple nuclei and abnormal morphology emerge.…”

Section: Introductionmentioning

confidence: 99%

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

et al. 2018

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The major goal of radiotherapy is the induction of tumor cell death. Additionally, radiotherapy can function as in situ cancer vaccination by exposing tumor antigens and providing adjuvants for anti-tumor immune priming. In this regard, the mode of tumor cell death and the repertoire of released damage-associated molecular patterns (DAMPs) are crucial. However, optimal dosing and fractionation of radiotherapy remain controversial. Here, we examined the initial steps of anti-tumor immune priming by different radiation regimens (20 Gy, 4 × 2 Gy, 2 Gy, 0 Gy) with cell lines of triple-negative breast cancer in vitro and in vivo. Previously, we have shown that especially high single doses (20 Gy) induce a delayed type of primary necrosis with characteristics of mitotic catastrophe and plasma membrane disintegration. Now, we provide evidence that protein DAMPs released by these dying cells stimulate sequential recruitment of neutrophils and monocytes in vivo. Key players in this regard appear to be endothelial cells revealing a distinct state of activation upon exposure to supernatants of irradiated tumor cells as characterized by high surface expression of adhesion molecules and production of a discrete cytokine/chemokine pattern. Furthermore, irradiated tumor cell-derived protein DAMPs enforced differentiation and maturation of dendritic cells as hallmarked by upregulation of co-stimulatory molecules and improved T cell-priming. Consistently, a recurring pattern was observed: The strongest effects were detected with 20 Gy-irradiated cells. Obviously, the initial steps of radiotherapy-induced anti-tumor immune priming are preferentially triggered by high single doses – at least in models of triple-negative breast cancer.

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The essence of senescence: Figure 1.

Cited by 1,748 publications

References 207 publications

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

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The essence of senescence: Figure 1.

Cited by 1,748 publications

References 207 publications

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

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CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a