2006
DOI: 10.1038/ncb1471
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Abstract: Dysfunction of the endoplasmic reticulum (ER) has been reported in a variety of human pathologies, including cancer. However, the contribution of the ER to the early stages of normal cell transformation is largely unknown. Using primary human melanocytes and biopsies of human naevi (moles), we show that the extent of ER stress induced by cellular oncogenes may define the mechanism of activation of premature senescence. Specifically, we found that oncogenic forms of HRAS (HRAS(G12V)) but not its downstream targ… Show more

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Cited by 299 publications
(311 citation statements)
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“…This occurred in the absence of any detectable increase in cell death, as assessed by flow cytometry. Cultures of MCF7 and T47D cells depleted of PKCi also showed a decrease in the percentage of cells incorporating 5-bromodeoxyuridine (BrdU), consistent with decreased cell division causing the decrease in viable cell numbers observed (Figure 3c DNA damage (either telomeric in the case of replicative senescence or non-telomeric in the case of premature senescence) is a common, although not universally observed (Denoyelle et al, 2006;Lin et al, 2010), feature of senescence and DNA-damage responses have an important role in the initiation and maintenance of the senescent phenotype . To assay whether DNA-damage response pathways were activated upon PKCi depletion in breast cancer cells, the presence of gH2AX foci was assessed by immunofluorescence microscopy.…”
Section: Pik3ca Mutations Increase the Expression And Activation Of Pkcimentioning
confidence: 71%
See 1 more Smart Citation
“…This occurred in the absence of any detectable increase in cell death, as assessed by flow cytometry. Cultures of MCF7 and T47D cells depleted of PKCi also showed a decrease in the percentage of cells incorporating 5-bromodeoxyuridine (BrdU), consistent with decreased cell division causing the decrease in viable cell numbers observed (Figure 3c DNA damage (either telomeric in the case of replicative senescence or non-telomeric in the case of premature senescence) is a common, although not universally observed (Denoyelle et al, 2006;Lin et al, 2010), feature of senescence and DNA-damage responses have an important role in the initiation and maintenance of the senescent phenotype . To assay whether DNA-damage response pathways were activated upon PKCi depletion in breast cancer cells, the presence of gH2AX foci was assessed by immunofluorescence microscopy.…”
Section: Pik3ca Mutations Increase the Expression And Activation Of Pkcimentioning
confidence: 71%
“…We did not see any evidence for activation of the DNA-damage response with PKCi depletion in either breast cancer or glioblastoma cells. Other groups have also described senescence that occurs in the absence of detectable DNA-damage response pathway activation (Denoyelle et al, 2006;Lin et al, 2010). The lack of a requirement for p53 and p16, along with the absence of activation of a DNA-damage response, suggests a novel mechanism for senescence induction upon PKCi depletion.…”
Section: Discussionmentioning
confidence: 99%
“…Senescence has been most widely studied in fibroblasts in vitro, but is also well-defined in melanocytes and epithelial cells (35,79,135). Other cell types suggested to undergo senescence include hematopoietic and neural progenitor cells (46,91).…”
Section: Molecular Characteristics Of Senescencementioning
confidence: 99%
“…In mouse cells, SAHF should not be confused with the highly-condensed domains of constitutive pericentromeric heterochromatin that are present even in growing mouse cells (53). Of human cells, WI38 and IMR90 fibroblasts and primary human melanocytes form pronounced SAHF, whereas BJ fibroblasts form less marked SAHF (35,88). In response to an activated Ras oncogene, primary human melanocytes express SA β-gal and assume the classical large, flat extensively-vacuolarized morphology.…”
Section: Molecular Characteristics Of Senescencementioning
confidence: 99%
“…Importantly, N-Ras also localises to mitochondria and cells lacking N-Ras or K(B)-Ras display abnormal mitochondrial morphology [105]. Analogous to this role in modifying organelle structure, overexpression of activated H-Ras but not other Ras isoforms causes gross vacuolarisation and expansion of the ER resulting in cell cycle arrest [106]. Finally, an H-Ras splice variant, p19 ras , is localised to the cytosol and nucleus because it lacks the C-terminal HVR [107].…”
Section: Compartmentalised Ras Signallingmentioning
confidence: 99%