Myc Down-regulation as a Mechanism to Activate the Rb Pathway in STAT5A-induced Senescence

Mallette, Frédérick A.; Gaumont-Leclerc, Marie-France; Huot, Geneviève; Ferbeyre, Gerardo

doi:10.1074/jbc.m707074200

Cited by 44 publications

(48 citation statements)

References 52 publications

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“…These oncogenes are able to transform cells, but only in collaboration with other oncogenes such as MYC (31,32). Similar results have been described for ectopic expression of other components of the RAS pathway, such as RAC1 and RAF (33,34), as well as other oncogenes, including E2F and STAT5A (35,36). Although, in most studies, these experiments were conducted in primary fibroblasts or other primary cell lines, oncogene-induced senescence has also been described in tumor cell lines (37,38).…”

Section: Discussionsupporting

confidence: 70%

Regulation of Cell Cycle Genes and Induction of Senescence by Overexpression of OTX2 in Medulloblastoma Cell Lines

Bunt

Haas

Hasselt

et al. 2010

Molecular Cancer Research

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The transcription factor orthodenticle homeobox 2 (OTX2) has been implicated in the pathogenesis of medulloblastoma, as it is often highly expressed and sometimes amplified in these tumors. Little is known of the downstream pathways regulated by OTX2. We therefore generated MED8A and DAOY medulloblastoma cell lines with doxycycline-inducible OTX2 expression. In both cell lines, OTX2 inhibited proliferation and induced a senescencelike phenotype with senescence-associated β-galactosidase activity. Expression profiles of time series after OTX2 induction in MED8A showed early upregulation of cell cycle genes related to the G 2 -M phase, such as AURKA, CDC25C, and CCNG2. Paradoxically, G 1 -S phase genes such as MYC, CDK4, CDK6, CCND1, and CCND2 were strongly downregulated, in line with the observed G 1 arrest. ChIP-on-chip analyses of OTX2 binding to promoter regions in MED8A and DAOY showed a strong enrichment for binding to the G 2 -M genes, suggesting a direct activation. Their mRNA expression correlated with OTX2 expression in primary tumors, underscoring the in vivo relevance of this regulation. OTX2 induction activated the P53 pathway in MED8A, but not in DAOY, which carries a mutated P53 gene. In DAOY cells, senescence-associated secretory factors, such as interleukin-6 and insulin-like growth factor binding protein 7, were strongly upregulated after OTX2 induction. We hypothesize that the imbalance in cell cycle stimulation by OTX2 leads to cellular senescence either by activating the P53 pathway or through the induction of secretory factors. Our data indicate that OTX2 directly induces a series of cell cycle genes but requires cooperating genes for an oncogenic acceleration of the cell cycle.

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Section: Discussionsupporting

confidence: 70%

Regulation of Cell Cycle Genes and Induction of Senescence by Overexpression of OTX2 in Medulloblastoma Cell Lines

Bunt

Haas

Hasselt

et al. 2010

Molecular Cancer Research

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“…Ras-induced senescence in human cells can be mediated by either the p53 or the Rb family of tumor suppressors (28,29,43,48). This means that oncogenic ras can trigger senescence in human cells where p53 or Rb is disabled but cannot do it if both pathways are inhibited.…”

Section: Resultsmentioning

confidence: 99%

“…Some oncogenes, such as RasV12, STAT5, and Bcl2, have antiapoptotic activity, and some cell types have a high apoptosis threshold. Another tumor suppressor response, called cellular senescence, serves as a fail-safe mechanism against the transforming activity of antiapoptotic oncogenes (29,40,43). However, currently it is unknown whether mitochondria also can play a role in oncogene-induced senescence (OIS).…”

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confidence: 99%

Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence

Moiseeva

Bourdeau

Roux

et al. 2009

Molecular and Cellular Biology

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339

263

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The expression of oncogenic ras in normal human cells quickly induces an aberrant proliferation response that later is curtailed by a cell cycle arrest known as cellular senescence. Here, we show that cells expressing oncogenic ras display an increase in the mitochondrial mass, the mitochondrial DNA, and the mitochondrial production of reactive oxygen species (ROS) prior to the senescent cell cycle arrest. By the time the cells entered senescence, dysfunctional mitochondria accumulated around the nucleus. The mitochondrial dysfunction was accompanied by oxidative DNA damage, a drop in ATP levels, and the activation of AMPK. The increase in mitochondrial mass and ROS in response to oncogenic ras depended on intact p53 and Rb tumor suppression pathways. In addition, direct interference with mitochondrial functions by inhibiting the expression of the Rieske iron sulfur protein of complex III or the use of pharmacological inhibitors of the electron transport chain and oxidative phosphorylation was sufficient to trigger senescence. Taking these results together, this work suggests that mitochondrial dysfunction is an effector pathway of oncogene-induced senescence.Mitochondria are central to cell metabolism and energy production. High-energy electrons coming from the oxidation of different carbon sources such as glucose and fatty acids enter the mitochondrial electron transport chain as reduced equivalents, and their energy gradually is converted into a proton gradient. Mitochondria use this gradient to synthesize ATP that later is used for biosynthetic reactions (9, 30). Mitochondria also control decisions for life and death. Changes in mitochondrial membrane permeability lead to the release of proapoptotic mediators that can kill cells with DNA damage or activated oncogenes (16). In this way, mitochondria control one of the major tumor suppressor responses: apoptosis (27). Some oncogenes, such as RasV12, STAT5, and Bcl2, have antiapoptotic activity, and some cell types have a high apoptosis threshold. Another tumor suppressor response, called cellular senescence, serves as a fail-safe mechanism against the transforming activity of antiapoptotic oncogenes (29,40,43). However, currently it is unknown whether mitochondria also can play a role in oncogene-induced senescence (OIS).OIS is phenotypically similar to the senescence response triggered by short telomeres, also known as replicative senescence (6). Replicative senescence is, in essence, the consequence of a DNA damage response triggered by short telomeres (11). OIS also involves the DNA damage response (2, 15, 28), but the mechanism of DNA damage and the contribution of mitochondria to it are unclear. It has been demonstrated that mitochondria play a critical role in replicative senescence, and several mitochondrial changes, including an increase in the production of reactive oxygen species (ROS), were reported in cells with short telomeres (34, 35). Mitochondrion-derived ROS contribute to the senescent phenotype by damaging the DNA (35) and therefore amplifyin...

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“…In aged human ADSCs, c-myc is down-regulated similar to other senescent cell types (Mallette et al 2007). All mentioned features were accompanied by telomere shortening.…”

Section: Adscs Harvesting Isolation and Culturingmentioning

confidence: 99%

Isolation, Culturing, Characterization and Aging of Adipose Tissue-derived Mesenchymal Stem Cells: A Brief Overview

Fathi

Farahzadi

2016

Braz. arch. biol. technol.

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The aim of this review was to describe the current state-of-the-art regarding isolation, characterization and aging of adipose tissue-derived mesenchymal stem cells (ADSCs). Mesenchymal stem cells (MSCs) have recently received widespread attention because of their potential use in tissue-engineering applications. Various studies have indicated that MSCs with a fibroblast-like morphology migrate to the sites of injury and help to regenerate damaged tissue. Over the past few years, it has been recognized that fat is not only an energy supply, but also a rich source of multipotent stem cells that can be easily harvested, isolated and selected as compared with other tissues. ADSCs are particularly interesting because of their rapid proliferation and multidirectional differentiation potential.

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Myc Down-regulation as a Mechanism to Activate the Rb Pathway in STAT5A-induced Senescence

Cited by 44 publications

References 52 publications

Regulation of Cell Cycle Genes and Induction of Senescence by Overexpression of OTX2 in Medulloblastoma Cell Lines

Regulation of Cell Cycle Genes and Induction of Senescence by Overexpression of OTX2 in Medulloblastoma Cell Lines

Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence

Isolation, Culturing, Characterization and Aging of Adipose Tissue-derived Mesenchymal Stem Cells: A Brief Overview

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