Dual roles of ERK1/2 in cellular senescence induced by excess thymidine in HeLa cells

Kudo, Ikuru; Nozawa, Megumi; Miki, Kensuke; Takauji, Yuki; En, Atsuki; Fujii, Michihiko; Ayusawa, Dai

doi:10.1016/j.yexcr.2016.07.018

Cited by 6 publications

(6 citation statements)

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“…This seemed to be in line with previous studies in renal epithelial cells where apoptosis decreased if ERK was blocked [31, 32], but contrary with our previous research that TGF-β1 could enhance the expression level of p-ERK to inhibit autophagy and apoptosis in AF cells under serum deprivation in vitro [14]. This may be attributed to the dual roles of ERK1/2 [33]. Moreover, apoptosis and autophagy are two main programmed cell death patterns and closely linked [34].…”

Section: Discussionsupporting

confidence: 87%

TGF-β1 reduces the oxidative stress-induced autophagy and apoptosis in rat annulus fibrosus cells through the ERK signaling pathway

Shen

Wang

et al. 2019

J Orthop Surg Res

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Background The aim of this study is to explore the effects of TGF-β1 on autophagy and apoptosis induced by exogenous hydrogen peroxide (H 2 O 2 ) in annulus fibrosus (AF) cells and possible signal pathways involved in this process. Methods AF cells were isolated from rat lumbar discs and subjected to different concentrations of exogenous H 2 O 2 (50, 100, 200 μmol/L) for different time periods (0.5, 1, 2, and 4 h). Cell viability was determined by CCK-8 assay, and the levels of autophagy and apoptosis were evaluated by Western blotting and caspase 3, 8, 9 activity assay. By administration with different concentrations of TGF-β1 (5, 10, 20 ng/mL), the effects of TGF-β1 on autophagy and apoptosis induced by H 2 O 2 were observed, and the possible signaling pathways were also investigated by using various apoptosis inhibitors or an autophagy inhibitor Bafilomycin A (Baf A) in AF cells. Results H 2 O 2 significantly impaired cell viability in a dose- and time-dependent manner. H 2 O 2 also induced a sudden and the highest level of autophagy at 1 h, and gradually increased apoptosis through ERK pathway. The mitochondrial pathway was involved in H 2 O 2 -induced apoptosis in AF cells. TGF-β1 reduced the expression of p-ERK and downregulated the expressions of Beclin-1, LC3 II/I, and mitochondrial-related apoptotic proteins (Bax/Bcl-2, caspase-9). Meanwhile, TGF-β1 downregulated the level of intracellular H 2 O 2 through upregulating the expression level of glutathione peroxidase-1 (GPx-1). Conclusions TGF-β1 reduced autophagy and apoptosis induced by exogenous H 2 O 2 through downregulating the expression of ERK in AF cells. TGF-β1 could downregulate the level of ERK and intracellular H 2 O 2 by upregulating GPx-1.

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Section: Discussionsupporting

confidence: 87%

TGF-β1 reduces the oxidative stress-induced autophagy and apoptosis in rat annulus fibrosus cells through the ERK signaling pathway

Shen

Wang

et al. 2019

J Orthop Surg Res

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“…At the same time, in cells expressing Ras or Raf mutants, ERK1/2 hyperactivation results in growth arrest [34]. Recently, the prolonged induction of ERK1/2 was found to contribute to the development of a senescence phenotype in HeLa cells [35]. Surprisingly, AP-1, which is generally characterized as pro-mitotic, has also been reported as increased in senescent pEOCs [36].…”

Section: Discussionmentioning

confidence: 99%

Deciphering the Molecular Mechanism of Spontaneous Senescence in Primary Epithelial Ovarian Cancer Cells

Pakuła

Mały

Uruski

et al. 2020

Cancers

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Spontaneous senescence of cancer cells remains a puzzling and poorly understood phenomenon. Here we comprehensively characterize this process in primary epithelial ovarian cancer cells (pEOCs). Analysis of tumors from ovarian cancer patients showed an abundance of senescent cells in vivo. Further, serially passaged pEOCs become senescent after a few divisions. These senescent cultures display trace proliferation, high expression of senescence biomarkers (SA-β-Gal, γ-H2A.X), growth-arrest in the G1 phase, increased level of cyclins D1, D2, decreased cyclin B1, up-regulated p16, p21, and p53 proteins, eroded telomeres, reduced activity of telomerase, predominantly non-telomeric DNA damage, activated AKT, AP-1, and ERK1/2 signaling, diminished JNK, NF-κB, and STAT3 pathways, increased formation of reactive oxygen species, unchanged activity of antioxidants, increased oxidative damage to DNA and proteins, and dysfunctional mitochondria. Moreover, pEOC senescence is inducible by normal peritoneal mesothelium, fibroblasts, and malignant ascites via the paracrine activity of GRO-1, HGF, and TGF-β1. Collectively, pEOCs undergo spontaneous senescence in a mosaic, telomere-dependent and telomere-independent manner, plausibly in an oxidative stress-dependent mechanism. The process may also be activated by extracellular stimuli. The biological and clinical significance of pEOC senescence remains to be explored.

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“…Coordinated regulation of protein synthesis and degradation is important for the maintenance of proteostasis. Mammalian cells slow down DNA synthesis but continue protein synthesis when treated with stresses; then they accumulate proteins and undergo unbalanced growth, which eventually leads to cellular senescence [4][5][6][7][8]10]. Therefore, protein accumulation (loss of proteostasis) appears to be one of the important factors that induce cellular senescence.…”

Section: Discussionmentioning

confidence: 99%

“…Mammalian cells, when treated with the stresses, slow down DNA synthesis but continue protein synthesis, and undergo the phenomenon termed unbalanced growth, which is characterized by an accumulation of proteins . Importantly, we have shown that prolonged unbalanced growth leads to cellular senescence , and mild restriction of protein synthesis with a low dose of cycloheximide (CHX) suppresses protein accumulation and consequently prevents the induction of cellular senescence by the stresses . Moreover, mild restriction of protein synthesis extends not only the replicative life span of normal primary human fibroblasts but also the life span of the nematode Caenorhabditis elegans .…”

mentioning

confidence: 99%

“…Importantly, we have shown that prolonged unbalanced growth leads to cellular senescence [4,5,8], and mild restriction of protein synthesis with a low dose of cycloheximide (CHX) [9] suppresses protein accumulation and consequently prevents the induction of cellular senescence by the stresses [10,11]. Moreover, mild restriction of protein synthesis extends not only the replicative life span of normal primary human fibroblasts but also the life span of the nematode Caenorhabditis elegans [10,11].…”

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confidence: 99%

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Lamin B receptor plays a key role in cellular senescence induced by inhibition of the proteasome

Takauji

Miki

et al. 2020

FEBS Open Bio

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Cellular senescence is a terminal growth arrest phenomenon in mammalian cells. Coordinated regulation of protein synthesis and degradation is required to maintain protein homeostasis in cells; however, senescent cells exhibit decreased activity of the proteasome, a major cellular proteolytic machinery, with an accumulation of proteins. Indeed, we showed that MG132, a proteasome inhibitor, induced cellular senescence through an accumulation of proteins in human cells. We then investigated the mechanisms of cellular senescence induced by protein accumulation by treating cells with MG132. We found that lamin B receptor (LBR), a nuclear membrane protein that regulates heterochromatin organization, was mislocalized and down‐regulated in cells on treatment with MG132. Importantly, enforced expression of LBR suppressed cellular senescence induced by MG132. We also showed that LBR was involved in the regulation of chromatin organization in senescent cells, and that endoplasmic reticulum stress and autophagy were likely to be involved in the mislocalization and down‐regulation of LBR. These findings indicate that decreased LBR function was responsible for the induction of cellular senescence by MG132, and thus suggest that protein accumulation caused by inhibition of the proteasome induced cellular senescence probably through chromatin dysregulation in human cells.

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Dual roles of ERK1/2 in cellular senescence induced by excess thymidine in HeLa cells

Cited by 6 publications

References 50 publications

TGF-β1 reduces the oxidative stress-induced autophagy and apoptosis in rat annulus fibrosus cells through the ERK signaling pathway

TGF-β1 reduces the oxidative stress-induced autophagy and apoptosis in rat annulus fibrosus cells through the ERK signaling pathway

Deciphering the Molecular Mechanism of Spontaneous Senescence in Primary Epithelial Ovarian Cancer Cells

Lamin B receptor plays a key role in cellular senescence induced by inhibition of the proteasome

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