p53 Protein-mediated Up-regulation of MAP Kinase Phosphatase 3 (MKP-3) Contributes to the Establishment of the Cellular Senescent Phenotype through Dephosphorylation of Extracellular Signal-regulated Kinase 1/2 (ERK1/2)

Zhang, Hui; Chi, Yuan; Gao, Kun; Zhang, Xiling; Yao, Jian

doi:10.1074/jbc.m114.590943

Cited by 27 publications

(29 citation statements)

References 55 publications

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“…The MAPK family (JNK1/2, p38 and ERK1/2) respond to several types of stress and transduce signals to p53 phosphorylation on various sites [34]. However, ERK1/2 is different from the other two pathways, as its activation is regulated by p53-mediated MKP-3 transcription, and MKP-3 works as a specific ERK1/2 diphosphatase [11]. Consistent with these pathways, we showed that accumulated p53 decreased ERK1/2.…”

Section: Discussionsupporting

confidence: 70%

“…By contrast, senescent cells express a higher level of p53, which induces cell cycle arrest. p53 induces cell cycle arrest through both transcriptional activation of p21 and inactivation of extracellular signal-regulated kinase (ERK)1/2, which lead to inhibition of cyclin/cyclin dependent kinase (CDK) expression and combination [11][12][13]. In addition, p53 targets apoptosis-related genes, such as Bax and p53 upregulated modulator of apoptosis (PUMA), which evoke cytochrome C leakage from mitochondria and following apoptosis [14].…”

Section: Introductionmentioning

confidence: 99%

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Novel Role of p53 in Septic Immunosuppression: Involvement in Loss and Dysfunction of CD4+ T Lymphocytes

Zhang

Ren

et al. 2018

Cell Physiol Biochem

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Background/Aims: Immunosuppression frequently occurs during the development of sepsis and is closely associated with poor outcome. Characteristics of immunosuppressive CD4⁺ T lymphocytes in sepsis have been reported to include dramatic cell loss and inactivation. p53 acts as a pivotal transcription factor in regulating cell proliferation and apoptosis, which control tumorigenesis. However, few studies have investigated the universal role of p53 in immune cells, especially in the development of sepsis. Methods: A mouse model of sepsis was produced by cecal ligation and puncture (CLP), and isolated splenic CD4⁺ T cells or Jurkat cells were exposed to lipopolysaccharide (LPS) stimulation in vitro. We used genetic knockout (p53^-/-) mice or the specific inhibitor pifithrin-α (PFT) to investigate the regulatory mechanisms of p53. Cell proliferation ability was assessed using a Cell Counting Kit-8 assay, and apoptotic cells were stained with annexin V/propidium iodide and then analyzed using a FACScan flow cytometer. Protein and mRNA expression levels were measured by western blotting and real-time PCR, and cytokine levels in culture supernatants were determined by enzyme-linked immunosorbent assay. Results: Splenic CD4⁺ T lymphocytes from CLP mice expressed gradually elevated p53 mRNA and protein levels, which resulted in extracellular regulated protein kinase 1/2 inactivation and expression of apoptotic molecules. Specific inhibition of p53 by PFT or genetic knockout (p53^-/-) maintained CD4⁺ T lymphocyte homeostasis, as indicated by protection from cell loss and restoration of immune function. A medium dose of PFT improved the survival rate of mice, while mortality rate showed only a slight improvement in p53^-/- mice compared with wild-type mice. The in vitro responses to LPS were consistent with these results, and upregulation of p53 clearly affected the proliferation, apoptosis, and immune dysfunction of CD4⁺ T lymphocytes. In addition, we confirmed the regulatory effect of p53 in Jurkat cells, and inhibition of p53 by either inhibition or short hairpin RNA transduction markedly protected cells from LPS stimulation. Conclusion: Elevation of p53 in T lymphocytes during sepsis or endotoxin challenge might be responsible for inhibiting cell proliferation and enhancing both apoptosis and immune dysfunction of T cells.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Novel Role of p53 in Septic Immunosuppression: Involvement in Loss and Dysfunction of CD4+ T Lymphocytes

Zhang

Ren

et al. 2018

Cell Physiol Biochem

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“…A previous study showed that DUSP6 negatively and specifically modulated ERK1/2 kinase activity34. It has also been reported that down-regulation of DUSP6 expression is involved in drug resistance in ovarian cancer35, and up-regulation of DUSP6 mediated by p53 caused a cellular senescent phenotype36. Taken together with our results, these findings suggest that increased ERK1/2 phosphorylation in pazopanib-resistant SS cells is at least in part due to down-regulation of DUSP6 expression.…”

Section: Discussionsupporting

confidence: 86%

Activation of ERK1/2 Causes Pazopanib Resistance via Downregulation of DUSP6 in Synovial Sarcoma Cells

Yokoyama

Matsunobu

Matsumoto

et al. 2017

Sci Rep

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Synovial sarcoma (SS) is a rare high-grade malignant mesenchymal tumour with a relatively poor prognosis despite intensive multimodal therapy. Although pazopanib, a multi-kinase inhibitor, is often used for advanced SS, most cases eventually become resistant to pazopanib. In the present study, we investigated the mechanisms of acquired pazopanib resistance in SS. To examine acquired pazopanib resistance, two SS cell lines, SYO-1 and HS-SY-II, were isolated after multiple selection steps with increasing concentrations of pazopanib. SYO-1 was also used in vivo. Then, pazopanib-resistant clones were investigated to assess potential mechanisms of acquired pazopanib resistance. Stable pazopanib-resistant clones were established and exhibited enhanced cell cycle progression, cell growth with increased ERK1/2 phosphorylation, and higher sensitivity than parental cells to a MEK-inhibitor, trametinib, both in vitro and in vivo. Furthermore, addition of low-dose trametinib partially reversed the pazopanib resistance. In the pazopanib-resistant clones, dual specificity phosphatase 6 (DUSP6) was downregulated. Inhibition of DUSP6 expression in parental HS-SY-II cells partially recapitulated acquired pazopanib resistance. Acquired pazopanib resistance in SS was associated with activation of ERK1/2 through downregulation of DUSP6 expression. Simultaneous treatment with pazopanib and a MEK inhibitor could be a promising strategy to overcome pazopanib resistance in SS.

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“…DUSP6 counteracts Ras/Raf/MEK/ERK signaling by ERK1/2 desphosphorylation [23, 26]. In our study, it exerted tumor suppressive functions in all four cancer types analyzed.…”

Section: Discussionmentioning

confidence: 75%

Systematic screening of isogenic cancer cells identifies DUSP6 as context-specific synthetic lethal target in melanoma

et al. 2017

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Next-generation sequencing has dramatically increased genome-wide profiling options and conceptually initiates the possibility for personalized cancer therapy. State-of-the-art sequencing studies yield large candidate gene sets comprising dozens or hundreds of mutated genes. However, few technologies are available for the systematic downstream evaluation of these results to identify novel starting points of future cancer therapies.We improved and extended a site-specific recombination-based system for systematic analysis of the individual functions of a large number of candidate genes. This was facilitated by a novel system for the construction of isogenic constitutive and inducible gain-and loss-of-function cell lines. Additionally, we demonstrate the construction of isogenic cell lines with combinations of the traits for advanced functional in vitro analyses. In a proof-of-concept experiment, a library of 108 isogenic melanoma cell lines was constructed and 8 genes were identified that significantly reduced viability in a discovery screen and in an independent validation screen. Here, we demonstrate the broad applicability of this recombination-based method and we www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 14), pp: 23760-23774 Research PaperOncotarget 23761 www.impactjournals.com/oncotarget proved its potential to identify new drug targets via the identification of the tumor suppressor DUSP6 as potential synthetic lethal target in melanoma cell lines with BRAF V600E mutations and high DUSP6 expression.

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p53 Protein-mediated Up-regulation of MAP Kinase Phosphatase 3 (MKP-3) Contributes to the Establishment of the Cellular Senescent Phenotype through Dephosphorylation of Extracellular Signal-regulated Kinase 1/2 (ERK1/2)

Cited by 27 publications

References 55 publications

Novel Role of p53 in Septic Immunosuppression: Involvement in Loss and Dysfunction of CD4+ T Lymphocytes

Novel Role of p53 in Septic Immunosuppression: Involvement in Loss and Dysfunction of CD4+ T Lymphocytes

Activation of ERK1/2 Causes Pazopanib Resistance via Downregulation of DUSP6 in Synovial Sarcoma Cells

Systematic screening of isogenic cancer cells identifies DUSP6 as context-specific synthetic lethal target in melanoma

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