Modulation of Replicative Senescence of Diploid Human Cells by Nuclear ERK Signaling

Tresini, Maria; Lorenzini, Antonello; Torres, Claudio; Cristofalo, Vincent J.

doi:10.1074/jbc.m604955200

Cited by 58 publications

(53 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This finding is in line with the observation that elevated cytosolic levels of phosphorylated ERK1/2 are required for Ras-induced senescence (Gaumont-Leclerc et al, 2004), whereas nucleartargeted ERK1/2 delays the onset of senescence (Tresini et al, 2007). Retention of phospho-ERK1/2 in the cytoplasm might promote senescence through attenuating the phosphorylation of nuclear ERK targets, thus explaining why increased ERK activation is associated with induction of senescence (Blagosklonny, 2006a;Cagnol and Chambard, 2009).…”

Section: Downregulation Of Tacc3 Induces Cellular Senescence S Schmidsupporting

confidence: 85%

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

et al. 2010

View full text Add to dashboard Cite

Microtubule-interfering cancer drugs such as paclitaxel (PTX) often cause chemoresistance and severe side effects, including neurotoxicity. To explore potentially novel antineoplastic molecular targets, we investigated the cellular response of breast carcinoma cells to short hairpin(sh)RNA-mediated depletion of the centrosomal protein transforming acidic coiled coil (TACC) 3, an Aurora A kinase target expressed during mitosis. Unlike PTX, knockdown of TACC3 did not trigger a cell death response, but instead resulted in a progressive loss of the pro-apoptotic Bcl-2 protein Bim that links microtubule integrity to spindle poison-induced cell death. Interestingly, TACC3-depleted cells arrested in G 1 through a cellular senescence program characterized by the upregulation of nuclear p21 WAF , downregulation of the retinoblastoma protein and extracellular signal-regulated kinase 1/2, formation of HP1c (phospho-Ser83)-positive senescence-associated heterochromatic foci and increased senescence-associated b-galactosidase activity. Remarkably, the onset of senescence following TACC3 knockdown was strongly accelerated in the presence of non-toxic PTX concentrations. Thus, we conclude that mitotic spindle stress is a major trigger of premature senescence and propose that the combined targeting of the centrosomal Aurora A-TACC3 axis together with drugs interfering with microtubule dynamics may efficiently improve the chemosensitivity of cancer cells.

show abstract

Section: Downregulation Of Tacc3 Induces Cellular Senescence S Schmidsupporting

confidence: 85%

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Ectopic expression of DUSP4/MKP-2 in human diploid fibroblasts leads to premature replicative senescence, whereas inactivation of DUSP4/MKP-2 prohibits senescence (37). This activity is shared with other tumor suppressor genes, for example, p16INK4a (38,39) and p21/Waf/Sdi1, initially uncovered as a clone involved in the senescence of human diploid fibroblasts (40).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Downregulation of Mitogen-Activated Protein Kinase Phosphatase MKP-2 Relieves Its Growth Suppressive Activity in Glioma Cells

et al. 2010

View full text Add to dashboard Cite

Critical tumor suppression pathways in brain tumors have yet to be fully defined. Along with mutational analyses, genome-wide epigenetic investigations may reveal novel suppressor elements. Using differential methylation hybridization, we identified a CpG-rich region of the promoter of the dual-specificity mitogenactivated protein kinase phosphatase-2 gene (DUSP4/MKP-2) that is hypermethylated in gliomas. In 83 astrocytic gliomas and 5 glioma cell lines examined, hypermethylation of the MKP-2 promoter was found to occur relatively more frequently in diffuse or anaplastic astrocytomas and secondary glioblastomas relative to primary glioblastomas. MKP-2 hypermethylation was associated with mutations in TP53 and IDH1, exclusive of EGFR amplification, and with prolonged survival of patients with primary glioblastoma. Expression analysis established that promoter hypermethylation correlated with reduced expression of MKP-2 mRNA and protein. Consistent with a regulatory role, reversing promoter hypermethylation by treating cells with 5-aza-2′-deoxycytidine increased MKP-2 mRNA levels. Furthermore, we found that glioblastoma cell growth was inhibited by overexpression of exogenous MKP-2. Our findings reveal MKP-2 as a common epigenetically silenced gene in glioma, the inactivation of which may play a significant role in glioma development.

show abstract

“…Because MKP-1 mainly dephosphorylates JNK and p38 (40), which were only marginally altered in this investigation (data not shown), further study on this enzyme has not been done. There was one previous report demonstrating a key role of MKP-2 in impairment of nuclear ERK1/2 phosphorylation and function in replicative senescence (41). The question naturally occurs how two spatially differently located phosphatases exert similar effects on ERK1/2 activation and function.…”

Section: Discussionmentioning

confidence: 99%

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

Chi

Gao

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Growth arrest is a hallmark of cellular senescence. Results: Loss of cell proliferation in senescent cells was associated with impaired ERK1/2 activation, which was caused by p53-mediated elevation of MKP-3. Conclusion:The p53/MKP-3/ERK1/2 cascade contributed to the establishment of the senescent phenotype. Significance: Our study provides novel insights into the actions and mechanisms of p53 on cellular senescence.

show abstract

Modulation of Replicative Senescence of Diploid Human Cells by Nuclear ERK Signaling

Cited by 58 publications

References 91 publications

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

Epigenetic Downregulation of Mitogen-Activated Protein Kinase Phosphatase MKP-2 Relieves Its Growth Suppressive Activity in Glioma Cells

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)

Contact Info

Product

Resources

About