Inactivation of p38 kinase delays the onset of senescence in rabbit articuilar chondrocytes

Kang, Sangmo; Jung, Mun-Su; Kim, Chulwoo; Shin, Deug Y.

doi:10.1016/j.mad.2004.11.009

Cited by 19 publications

(14 citation statements)

References 35 publications

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“…Moreover, we observed that phosphorylation-mediated activation of p38 MAPK, but not of ERK1/2 or JNK1/2, significantly increased in adrenal glands from old animals. These data are consistent with the recent findings reported in other systems, where increased activation of p38 MAPK has been linked to various aging-induced alterations in metabolic parameters (Haq et al, 2002;Davis et al, 2005;Kang et al, 2005;Hsieh & Papaconstantinou, 2006;Ito et al, 2006). In the present study, we also observed an association between oxidative stress and p38 MAPK activation, raising the possibility that aging-induced enhanced oxidative stress leads to activation of p38 MAPK, which, in turn, attenuates the steroidogenic response seen during aging.…”

Section: Discussionsupporting

confidence: 94%

Evidence that age‐related changes in p38 MAP kinase contribute to the decreased steroid production by the adrenocortical cells from old rats

et al. 2007

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SummaryThe current studies were initiated to investigate whether excessive oxidative stress exerts its antisteroidogenic action through modulation of oxidant-sensitive mitogenactivated protein kinase (MAPK) signaling pathways. Western blot analysis indicated that aging caused increased phosphorylation and activation of rat adrenal p38 MAPK, but not the ERK1/2 or JNK1/2. Lipid peroxidation measurements (an index of cellular oxidative stress) indicated that adrenal membranes from young animals contained only minimal levels of endogenous thiobarbituric acid-reactive substances (TBARS), and exposure of membranes to enzymatic and non-enzymatic pro-oxidants enhanced TBARS formation approximately 12-and 20-fold, respectively. The adrenal membranes from old animals showed much more susceptibility to lipid peroxidation and exhibited roughly 4-to 6-fold higher TBARS formation than young controls both under basal conditions and in response to pro-oxidants. Qualitatively similar results were obtained when lipid peroxide formation was measured using a sensitive FOXRS (ferrous oxidation-xylenol orangereactive substances) technique. We next tested whether aging-induced excessive oxidative insult alters steroidogenesis through modulation of MAPK signaling pathway. Treatment of adrenocortical cells from old rats with specific p38 MAPK inhibitors restored Bt2cAMP-stimulated steroidogenesis ~60-70% of the value seen in cells of young animals. Likewise, pretreatment of cells with reactive oxygen species (ROS) scavengers MnTMPyP and N -acetyl cysteine also partially rescued age-induced loss of steroid production. In contrast, simultaneous treatment of cells with ROS scavengers and p38 MAPK inhibitor did not produce any additional effect suggesting that both types of inhibitors exert their stimulatory action through inhibition of p38 MAPK activation. Collectively, these results indicate that p38 MAPK functions as a signaling effector in oxidative stress-induced inhibition of steroidogenesis during aging.

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Section: Discussionsupporting

confidence: 94%

Evidence that age‐related changes in p38 MAP kinase contribute to the decreased steroid production by the adrenocortical cells from old rats

et al. 2007

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“…Recent studies have demonstrated that the phosphorylation of hnRNP A1 by the p38 MAPK pathway induced cytoplasmic accumulation 36,41,42. It has also been shown in senescent WI-38 fibroblasts and rabbit chondrocytes, that there is an upregulation of c-H-ras mRNA with a concomitant activation of p38 MAPK 39,40. These reports raised the possibility that an age-dependent change in hnRNP A1 localization and protein levels could be regulated by the Ras-p38 MAPK pathway.…”

Section: Resultsmentioning

confidence: 98%

p38 MAP Kinase-dependent regulation of the expression level and subcellular distribution of heterogeneous nuclear ribonucleoprotein A1 and its involvement in cellular senescence in normal human fibroblasts

Shimada¹,

Rios²,

Moran³

et al. 2009

RNA Biology

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Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a RNA binding protein that plays important role in the biogenesis of mRNA, such as alternative splicing and mRNA stability. We have previously demonstrated that hnRNP A1 has diminished protein levels and shows cytoplasmic accumulation in senescent human diploid fibroblasts. Recent reports showed that p38 MAP kinase (p38 MAPK), a member of the MAP kinase family is necessary and sufficient for the cytoplasmic accumulation of hnRNP A1 by stress stimuli such as osmotic shock. p38 MAP kinase has been shown to be involved in cell proliferation and the induction of senescence in response to extracellular stimuli. However, the relationship between hnRNP A1 and p38 MAPK and the roles of hnRNP A1 in cellular senescence have not yet been elucidated. Here we show that hnRNP A1 forms a complex with phospho-p38 MAPK in vivo. Inhibition of p38 MAPK activity with SB203580 elevated hnRNP A1 protein levels and prohibited the cytoplasmic accumulation of the protein, but not hnRNP A2, in senescent cells. The phosphorylation level of hnRNP A1 was elevated in senescent cells. Reduction of hnRNP A1 and A2 levels by siRNA transfection induced a senescence-like morphology and elevated the level of F-actin, a marker of senescence. These results suggest that the expression levels and subcellular distribution of hnRNP A1 are regulated in a p38 MAPK-dependent manner, probably via its phosphorylation. Our results also suggest that hnRNP A2 in addition to hnRNP A1 may play a role in establishing the senescence phenotype.

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“…In human fibroblasts undergoing replicative senescence, p38 was found to be activated, and expression of hTERT appeared to abrogate such p38 activation, suggesting that p38 is activated through telomere shortening [56]. In rabbit articular chondrocytes, inhibition of p38 activity by SB203580 or by expression of dominant negative MKK6 stimulated proliferation and partially delayed the onset of senescence [66]. These findings suggest that activation of the p38 pathway is involved in replicative senescence induced by telomere shortening.…”

Section: The P38 Pathway In Replicative Senescencementioning

confidence: 88%

Stress-Activated MAP Kinase Cascades in Cellular Senescence

Maruyama¹,

Naguro²,

Takeda³

et al. 2009

CMC

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In response to progressive telomere shortening in successive cell divisions, normal somatic cells withdraw from the cell cycle and exhibit irreversible growth arrest. This state, called cellular senescence, is induced not only by telomere shortening but also by various physico-chemical stressors that induce DNA damage and chromatin disruption as well as by strong mitogenic signals. Because senescent cells never re-enter the cell cycle, cellular senescence appears to prevent malignant transformation of damaged cells and thus contributes to tumor suppression. On the other hand, excess accumulation of senescent cells attenuates the integrity and normal function of tissues, leading to age-related diseases. In addition to the well-established roles of p53 and pRB in cellular senescence, recent evidence suggests that stress-activated mitogen-activated protein kinase (MAPK) cascades that converge on c-Jun N-terminal kinases (JNKs) and p38 MAPKs also play important roles in the regulation of cellular senescence. In this review, we focus on signaling that regulates stress-induced cellular senescence, with special focus on the JNK and p38 MAPK cascades.

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Inactivation of p38 kinase delays the onset of senescence in rabbit articuilar chondrocytes

Cited by 19 publications

References 35 publications

Evidence that age‐related changes in p38 MAP kinase contribute to the decreased steroid production by the adrenocortical cells from old rats

Evidence that age‐related changes in p38 MAP kinase contribute to the decreased steroid production by the adrenocortical cells from old rats

p38 MAP Kinase-dependent regulation of the expression level and subcellular distribution of heterogeneous nuclear ribonucleoprotein A1 and its involvement in cellular senescence in normal human fibroblasts

Stress-Activated MAP Kinase Cascades in Cellular Senescence

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