Rac1 GTPase Regulates Cell Genomic Stability and Senescence

Debidda, Marcella; Williams, David A.; Zheng, Yi

doi:10.1074/jbc.m604607200

Cited by 52 publications

(45 citation statements)

References 51 publications

(91 reference statements)

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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: 71%

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: 71%

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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“…13,14 It is possible that one of the subunits is compensated because of the loss of other subunits. Therefore, we determined the mRNA and protein levels of NADPH oxidase major components such as p47 phox , gp91…”

Section: Up-regulation Of Nox4 In Lungs Of P47 Phoxϫ/ϫ and Gp91 Phoxϫmentioning

confidence: 99%

“…Recent studies have shown that NADPH oxidase subunits are under tight regulatory control in physiological conditions. 13,14 For example, a specific disruption of Rac1 in mouse embryonic fibroblasts leads to an increase in ROS level that is attributable to a compensatory increase in Rac3, another component of NADPH oxidase. 13 Furthermore, Rac1 was up-regulated in hematopoietic cells deficient in Rac2.…”

Section: Cigarette Smoke (Cs) Induces Recruitment Of Inflammatory Celmentioning

confidence: 99%

Genetic Ablation of NADPH Oxidase Enhances Susceptibility to Cigarette Smoke-Induced Lung Inflammation and Emphysema in Mice

Yao

Edirisinghe

Yang

et al. 2008

The American Journal of Pathology

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Cigarette smoke (CS) induces recruitment of inflammatory cells in the lungs leading to the generation of reactive oxygen species (ROS), which are involved in lung inflammation and injury. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a multimeric system that is responsible for ROS production in mammalian cells. We hypothesized that NADPH oxidase-derived ROS play an important role in lung inflammation and injury and that targeted ablation of components of NADPH oxidase (p47 phox and gp91 phox ) would protect lungs against the detrimental effects of CS. To test this hypothesis, we exposed p47 phox؊/؊ and gp91 phox؊/؊ mice to CS and examined inflammatory response and injury in the lung. Surprisingly, although CS-induced ROS production was decreased in the lungs of p47 phox؊/؊ and gp91 phox؊/؊ mice compared with wild-type mice, the inflammatory response was significantly increased and was accompanied by development of distal airspace enlargement and alveolar destruction. This pathological abnormality was associated with enhanced activation of the TLR4-nuclear factor-B pathway in response to CS exposure in p47 phox؊/؊ and gp91 phox؊/؊ mice. This phenomenon was confirmed by in vitro studies in which treatment of peritoneal macrophages with a nuclear factor-B inhibitor reversed the CS-induced release of proinflammatory mediators. Thus, these data suggest that genetic ablation of components of NADPH oxidase enhances susceptibility to the proinflammatory effects of CS leading to airspace enlargement and alveolar damage.

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“…In this context, Rac1 regulates gene expression, cell cycle progression, cell spreading, rearrangement of the actin cytoskeleton, and activation of the nonphagocytic NADPH (22), while Rac2, besides controlling actin-mediated functions, is necessary for activation of phagocytic NADPH oxidase (3,18). The recent observation that fibroblasts lacking Rac1 upregulate Rac3 activation and cellular ROS suggests a potential role for this Rac family member in ROS synthesis (7). Mesangial cells express Rac1 (19,33), and this small GTPase is required for regulating angiotensin II-dependent ROS production (19), clearly suggesting that Rac1 can control ROS generation in this glomerular cell type.…”

mentioning

confidence: 99%

Integrin α1β1 Controls Reactive Oxygen Species Synthesis by Negatively Regulating Epidermal Growth Factor Receptor-Mediated Rac Activation

Chen¹,

Abair²,

Ibanez³

et al. 2007

Molecular and Cellular Biology

100

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Integrins control many cell functions, including generation of reactive oxygen species (ROS) and regulation of collagen synthesis. Mesangial cells, found in the glomerulus of the kidney, are able to produce large amounts of ROS via the NADPH oxidase. We previously demonstrated that integrin ␣1-null mice develop worse fibrosis than wild-type mice following glomerular injury and this is due, in part, to excessive ROS production by ␣1-null mesangial cells. In the present studies, we describe the mechanism whereby integrin ␣1-null mesangial cells produce excessive ROS. Integrin ␣1-null mesangial cells have constitutively increased basal levels of activated Rac1, which result in its increased translocation to the cell membrane, excessive ROS production, and consequent collagen IV deposition. Basal Rac1 activation is a direct consequence of ligand-independent increased epidermal growth factor receptor (EGFR) phosphorylation in ␣1-null mesangial cells. Thus, our study demonstrates that integrin ␣1␤1-EGFR cross talk is a key step in negatively regulating Rac1 activation, ROS production, and excessive collagen synthesis, which is a hallmark of diseases characterized by irreversible fibrosis.Integrin ␣1␤1, a major collagen binding receptor, is expressed in different cell types, including fibroblasts (45), endothelial cells (8), and mesangial cells in the glomerulus of the kidney (30, 53). Integrin ␣1␤1 confers the ability of cells to bind to collagenous substrata, including collagens I and IV (4, 45), and to proliferate on these substrata (45). Moreover, cells expressing integrin ␣1␤1 sense extracellular levels of collagen and downregulate its synthesis at both transcriptional and translational levels (4,14). Finally, we demonstrated that integrin ␣1␤1 also downregulates the production of reactive oxygen species (ROS) (4, 58).Following renal injury, mice lacking integrin ␣1␤1 develop more extensive glomerular fibrosis characterized by excessive accumulation of collagen type IV compared to wild-type (WT) mice (4, 58). Increased fibrosis is due to both a direct effect of the lack of integrin ␣1␤1-mediated downregulation of collagen IV synthesis and excessive ROS production by ␣1-null mesangial cells.Constitutive production of ROS by mesangial cells, a major cell type found in the glomerulus of the kidney, originates from an intrinsic NADPH oxidase (26, 48) that normally functions at a low level and increases in response to inflammatory stimuli, high glucose, or stress (25,34,35,37,55). The NADPH oxidase, highly characterized in phagocytes, is a multicomponent enzyme complex that consists of the membrane-bound cytochrome b 558 (p22 phox and gp91 phox ) and cytoplasmic proteins (p40 phox , p47 phox , p67 phox ) that translocate to the membrane following cellular stimulation to produce superoxide (3, 9, 47). A multicomponent phagocyte-like NADPH oxidase is also a major source of ROS in many nonphagocytic cells, including mesangial cells. In the phagocyte-like NADPH oxidase, the catalytic subunits are termed Nox proteins, with ...

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Rac1 GTPase Regulates Cell Genomic Stability and Senescence

Cited by 52 publications

References 51 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

Genetic Ablation of NADPH Oxidase Enhances Susceptibility to Cigarette Smoke-Induced Lung Inflammation and Emphysema in Mice

Integrin α1β1 Controls Reactive Oxygen Species Synthesis by Negatively Regulating Epidermal Growth Factor Receptor-Mediated Rac Activation

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