Mitogen‐activated protein kinase p38 defines the common senescence‐signalling pathway

Iwasa, Hiroaki; Han, Jiahuai; Ishikawa, Fuyuki

doi:10.1046/j.1365-2443.2003.00620.x

Cited by 343 publications

(308 citation statements)

References 41 publications

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“…The lack of involvement of p53 in BU-induced senescence prompted us to hypothesize that activation of the Erk-p38 MAPK pathway may mediate the induction, because activation of the Erk-p38 MAPK pathway has also been implicated in the induction of cellular senescence [13,15,34,35]. Indeed, it was found that treatment of WI38 cells with BU activated Erk and p38 in a time-dependent manner and inhibition of Erk or p38 with a specific inhibitor significantly suppressed BU-induced WI38 cell senescence.…”

Section: Discussionmentioning

confidence: 99%

“…To elucidate the mechanisms of action whereby BU induces senescence, we first evaluated activation of the two key pathways that have been implicated in senescence induction: (1) the p53-p21 pathway triggered by DNA damage and (2) the p16-Rb pathway activated by the MAPK cascades [1,3,15,27]. The activation of these pathways was determined by analysis of phosphorylation of p53, Erk, p38, and JNK and expression of p21 and p16 using Western blot.…”

Section: Bu Induces Wi38 Cell Senescence Via the Erk-p38 Mapk Pathwaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Activation of p38 also contributes to the induction of senescence in response to DNA damage and telomere shortening [15]. Thus, it has been suggested that Erk and p38 may play a central role in mediating senescence induction by various stimuli including BU [15]. Although our previous studies showed that BU can selectively induce WI38 cell senescence through the Erk-p38 MAPK cascade [8], the mechanism by which BU activates Erk and p38 has yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Busulfan-induced senescence is dependent on ROS production upstream of the MAPK pathway

Probin

Wang

Zhou

2007

Free Radical Biology and Medicine

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Induction of cellular senescence is a common response of a normal cell to a DNA damaging agent, which may contribute to cancer chemotherapy-and ionizing radiation-induced normal tissue injury. The induction has been largely attributed to the activation of p53. However, the results from the present study suggest that busulfan (BU), an alkylating agent that causes DNA damage by crosslinking DNAs and DNA and proteins, induces senescence in normal human diploid WI38 fibroblasts through the extracellular signal-regulated kinase (Erk) and p38 mitogen-activated protein kinase (p38 MAPK) cascade independent of the p53-DNA damage pathway. The induction of WI38 cell senescence is initiated by a transient depletion of intracellular glutathione (GSH) and followed by a continuous increase in reactive oxygen species (ROS) production via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which leads to the activation of the Erk and p38 MAPK pathway. Incubation of WI38 cells with N-acetyl-cysteine (NAC) replenishes intracellular GSH; abrogates the increased production of ROS; ameliorates Erk and p38 MAPK activation; and attenuates senescence induction by BU. Thus, inhibition of senescence induction using a potent antioxidant or specific inhibitor of the Erk and p38 MAPK pathway has the potential to be developed as a mechanism-based strategy to ameliorate cancer therapy-induced normal tissue damage.

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Section: Discussionmentioning

confidence: 99%

Section: Bu Induces Wi38 Cell Senescence Via the Erk-p38 Mapk Pathwaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Busulfan-induced senescence is dependent on ROS production upstream of the MAPK pathway

Probin

Wang

Zhou

2007

Free Radical Biology and Medicine

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“…29,30 To explore the possible involvement of p38 MAPK in the induction of senescence-like phenotypes in Elongin A À/À MEFs, we examined the levels of total and activated p38 MAPK in passage to MEFs and E10.5 whole embryos. The total amounts of p38 MAPK were essentially the same; however, a significant increase in the amount of phosphorylated p38 MAPK was observed in Elongin A À/À MEFs (Figure 5c, left panel).…”

Section: Expression Of Hypoxia-response Genes Is Increased Inmentioning

confidence: 99%

Induction of apoptosis and cellular senescence in mice lacking transcription elongation factor, Elongin A

et al. 2006

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Elongin A is a transcription elongation factor that increases the overall rate of mRNA chain elongation by RNA polymerase II. To gain more insight into the physiological functions of Elongin A, we generated Elongin A-deficient mice. Elongin A homozygous mutant (Elongin A À/À ) embryos demonstrated a severely retarded development and died at between days 10.5 and 12.5 of gestation, most likely due to extensive apoptosis. Moreover, mouse embryonic fibroblasts (MEFs) derived from Elongin A À/À embryos exhibited not only increased apoptosis but also senescence-like growth defects accompanied by the activation of p38 MAPK and p53. Knockdown of Elongin A in MEFs by RNA interference also dramatically induced the senescent phenotype. A study using inhibitors of p38 MAPK and p53 and the generation of Elongin A-deficient mice with p53-null background suggests that both the p38 MAPK and p53 pathways are responsible for the induction of senescence-like phenotypes, whereas additional signaling pathways appear to be involved in the mediation of apoptosis in Elongin A À/À cells. Taken together, our results suggest that Elongin A is required for the transcription of genes essential for early embryonic development and downregulation of its activity is tightly associated with cellular senescence. Cell Death and Differentiation (2007) Eukaryotic mRNA synthesis by RNA polymerase II (pol II) is regulated by the concerted action of a set of transcription factors that control the activity of pol II during the initiation and elongation stages of transcription. At least six general transcription factors have been identified in eukaryotic cells and found to promote the selective binding of pol II to promoters and to support the basal level of transcription. 1 In addition, a diverse collection of elongation factors that promote efficient elongation of transcripts by pol II in vitro have also been identified. 2-4 These factors fall into two broad functional classes based on their ability to either reactivate arrested pol II or suppress the transient pausing of pol II. The first class is composed of members of the SII family. 3,5 The second class comprises a collection of elongation factors, including TFIIF, 6 Elongin, 7,8 ELL 9 and CSB, 10 which increase the overall rate of mRNA chain elongation by decreasing the frequency and/or duration of transient pausing of pol II at sites along the DNA template.Elongin was identified as a heterotrimer composed of A, B and C subunits of B770, 118 and 112 amino acids, respectively. 7,8,11,12 Elongin A is the transcriptionally active subunit, whereas Elongins B and C are positive regulatory subunits that can form an isolable Elongin BC subcomplex. 8,13,14 Although the functions of Elongin A in vivo remain largely unclear, Gerber et al. 15 have recently reported that the Drosophila homolog of Elongin A (dEloA) colocalizes with pol II at sites of active transcription on polytene chromosomes, and it also plays a critical role in heat shock gene expression in vivo. 15,16 Moreover, by the RNA interference (...

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Kinases and Cancer

Matthews¹,

Gerritsen²

2010

Targeting Protein Kinases for Cancer Therapy

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Mitogen‐activated protein kinase p38 defines the common senescence‐signalling pathway

Cited by 343 publications

References 41 publications

Busulfan-induced senescence is dependent on ROS production upstream of the MAPK pathway

Busulfan-induced senescence is dependent on ROS production upstream of the MAPK pathway

Induction of apoptosis and cellular senescence in mice lacking transcription elongation factor, Elongin A

Kinases and Cancer

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