Defective nuclear translocation of stress-activated signaling in senescent diploid human fibroblasts: a possible explanation for aging-associated apoptosis resistance

Kim, Sung Young; Ryu, Sangwon; Kang, Hyeran; Choi, Hae Ri; Park, Sang Chul

doi:10.1007/s10495-011-0612-2

Cited by 12 publications

(7 citation statements)

References 49 publications

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“…We observed that rate of B cell apoptosis declined with age, a phenomenon termed age related apoptosis resistance and already described for aged fibroblasts, which are less sensitive to apoptosis inducing agents as compared to young fibroblasts, possibly due to reduced translocation of stress induced signaling molecules into the nucleus [ 46 ]. Our data also show decreased rates of apoptosis among B cells in the spleens of old as compared to young rats independent of diet.…”

Section: Discussionmentioning

confidence: 90%

A sustained high fat diet for two years decreases IgM and IL-1 beta in ageing Wistar rats

et al. 2015

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BackgroundThe immune system undergoes several alterations of innate and adaptive immunity during ageing. The main features of the aged immune system are a reduced diversity of T cell receptors and a reduced activity of innate immune cells with subsequent changes in adaptive immunity resulting in a less effective, less specific, and dys-regulated immune response and in an increased susceptibility towards infection, malignancy, and autoimmunity. The process is referred to as immunosenescence and is also modulated by environmental modifiers, such as dietary factors. High fat diet (HFD), via direct modulation of immune cell function by fatty acids and/or increased body fat mass, influences immune function. However, it is not clear whether HFD is beneficial or detrimental for the functioning of the ageing immune system.MethodsMale Wistar rats fed with either a high fat diet (HFD 43 en% of fat) or control diet (SD, 25 en% of fat) over up to 24 month and were analyzed for plasma IL-1β, IL-6, TNF, IgM, IgG1, IgA, IgG2a, IgG2b, IgG2c, light chains lambda and kappa, testosterone, prolactin and percentage of splenic B cells and apoptosis rate, respectively.ResultsIn general, all analyzed immunoglobuline isotypes increased with age, except for IgA. This increase was attenuated by HFD. In HFD and SD rats the percentage of B cells in the spleen and also their apoptotic rate was lower in aged as compared to young animals with no additional diet-induced effect. Testosterone and prolactin levels were lower in old animals, as expected. There was a statistical trend towards an increased prolactin/testosterone ratio in middle aged (6–12 monthsnth) HFD rats as compared to SD. IL-6 was neither affected by HFD nor age. On the other hand, HFD rats showed a decrease in IL-1β as compared to SD, which correlated with the above-mentioned suppressive effect on immunoglobulin isotypes, especially IgM.ConclusionIn Wistar rats, HFD reveals an immunosuppressive effect in ageing animals by decreasing immunoglobulins, especially IgM, and IL-1β when compared to SD.

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Section: Discussionmentioning

confidence: 90%

A sustained high fat diet for two years decreases IgM and IL-1 beta in ageing Wistar rats

et al. 2015

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“…On the other hand, as demonstrated in the present study for extrinsic, cytokine-induced growth inhibition, and by others for intrinsic, oncogene-induced senescence [17,25], Ago2 nuclear translocation favors growth arrest. This is an interesting aspect as it is known that senescent cells are resistant to stimulusspecific apoptosis induction [32], but can be specifically cleared by targeted apoptosis induction using proapoptotic FOXO4-derived peptides [33].…”

Section: Discussionmentioning

confidence: 99%

Nuclear Translocation of Argonaute 2 in Cytokine-Induced Senescence

Rentschler

Chen

Pahl

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cellular senescence, or permanent growth arrest, is known as an effective tumor suppressor mechanism that can be induced by different stressors, such as oncogenes, chemotherapeutics or cytokine cocktails. Previous studies demonstrated that the growth-repressing state of oncogene-induced senescent cells depends on argonaute protein 2 (Ago2)-mediated transcriptional gene silencing and Ago2/Rb corepression of E2F-dependent cell cycle genes. Cytokine-induced senescence (CIS) likewise depends on activation of the p16^Ink4a/Rb pathway, and consecutive inactivation of the E2F family of transcription factors. In the present study, we therefore analyzed the role of Ago2 in CIS. Methods: Human cancer cell lines were treated with interferon-gamma (IFN-γ) and tumor necrosis factor (TNF) to induce senescence. Senescence was determined by growth assays and measurement of senescence-associated β-galactosidase (SA-β-gal) activity, Ago2 translocation by Ago2/ Ki67 immunofluorescence staining and western blot analysis, and gene transcription by quantitative polymerase chain reaction (qPCR). Results: IFN-γ and TNF permanently stopped cell proliferation and time-dependently increased SA-β-gal activity. After 24 – 48 h of cytokine treatment, Ago2 translocated from the cytoplasm into the nucleus of Ki67-negative cells, an effect which was shown to be reversible. Importantly, the proinflammatory cytokine cocktail suppressed Ago2-regulated cell cycle control genes, and siRNA-mediated depletion of Ago2 interfered with cytokine-induced growth inhibition. Conclusion: IFN-γ and TNF induce a stable cell cycle arrest of cancer cells that is accompanied by a fast nuclear Ago2 translocation and repression of Ago2-regulated cell cycle control genes. As Ago2 downregulation impairs cytokine-induced growth regulation, Ago2 may contribute to tissue homeostasis in human cancers.

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“…Two well established apoptotic inducers; Staurosporine [92] , [120] – [122] and Etoposide [91] , [123] were used in this study. Young (PD = 34) and aged (PD = 68) MRC-5 fibroblasts were treated with different concentrations of Staurosporine (0.1, 0.5, 1.0, 2.0 µM) or Etoposide (1.0, 2.5, 5.0, 7.5 µM) for different time spans (24, 48, 96 hrs) and maintained in culture at 20% O 2 .…”

Section: Methodsmentioning

confidence: 99%

Long-Term Quiescent Fibroblast Cells Transit into Senescence

et al. 2014

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Cellular senescence is described to be a consequence of telomere erosion during the replicative life span of primary human cells. Quiescence should therefore not contribute to cellular aging but rather extend lifespan. Here we tested this hypothesis and demonstrate that cultured long-term quiescent human fibroblasts transit into senescence due to similar cellular mechanisms with similar dynamics and with a similar maximum life span as proliferating controls, even under physiological oxygen conditions. Both, long-term quiescent and senescent fibroblasts almost completely fail to undergo apoptosis. The transition of long-term quiescent fibroblasts into senescence is also independent of HES1 which protects short-term quiescent cells from becoming senescent. Most significantly, DNA damage accumulates during senescence as well as during long-term quiescence at physiological oxygen levels. We suggest that telomere-independent, potentially maintenance driven gradual induction of cellular senescence during quiescence is a counterbalance to tumor development.

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Defective nuclear translocation of stress-activated signaling in senescent diploid human fibroblasts: a possible explanation for aging-associated apoptosis resistance

Cited by 12 publications

References 49 publications

A sustained high fat diet for two years decreases IgM and IL-1 beta in ageing Wistar rats

A sustained high fat diet for two years decreases IgM and IL-1 beta in ageing Wistar rats

Nuclear Translocation of Argonaute 2 in Cytokine-Induced Senescence

Long-Term Quiescent Fibroblast Cells Transit into Senescence

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