Cyclin G1 is involved in G2/M arrest in response to DNA damage and in growth control after damage recovery

Kimura, Shinya; Ikawa, Masahito; Ito, Akihiko; Okabe, Masaru; Nishimura, Hiroshi

doi:10.1038/sj.onc.1204270

Cited by 134 publications

(124 citation statements)

References 47 publications

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“…Cyclin G-deficient MEFs were shown to contain hyperphosphorylated Mdm2 and higher p53 levels when compared to cyclin G þ / þ MEFs (Kimura et al, 2001;Chen, 2002;Okamoto et al, 2002). Although the direct effects of cyclin G on the status of p53 phosphorylation have been unclear, recent studies demonstrated that cyclin G negatively regulates p53 stabilization by recruiting PP2A to dephosphorylate Mdm2 (Kimura et al, 2001;Chen, 2002;Okamoto et al, 2002). Consistent with previous studies, we found that loss of cyclin G enhanced phosphorylation of p53 at Ser-15 and promoted p53 stabilization.…”

supporting

confidence: 80%

“…Recent studies have demonstrated that cyclin G dephosphorylates Mdm2 by recruiting protein phosphatase 2A (PP2A), resulting in p53 stabilization (Okamoto et al, 1996(Okamoto et al, , 2002. Compared to cyclin G þ / þ cells, cyclin G-deficient cells exhibited a decrease in Mdm2 dephosphorylation and an increase in p53 protein levels (Kimura et al, 2001;Okamoto et al, 2002). It is also observed that cyclin Gmediated p53 stabilization is dependent upon Mdm2, yet, ubiquitination does not seem to be a main pathway of cyclin G-mediated p53 degradation (Ohtsuka et al, 2003).…”

mentioning

confidence: 84%

“…It has been speculated that the activated p53 and deactivated Mdm2 are the more phosphorylated forms of each protein (Maya et al, 2001;AlarconVargas and Ronai, 2002). Cyclin G-deficient MEFs were shown to contain hyperphosphorylated Mdm2 and higher p53 levels when compared to cyclin G þ / þ MEFs (Kimura et al, 2001;Chen, 2002;Okamoto et al, 2002). Although the direct effects of cyclin G on the status of p53 phosphorylation have been unclear, recent studies demonstrated that cyclin G negatively regulates p53 stabilization by recruiting PP2A to dephosphorylate Mdm2 (Kimura et al, 2001;Chen, 2002;Okamoto et al, 2002).…”

mentioning

confidence: 99%

“…These findings suggest that the negative effect of cyclin G on p53 regulation requires the presence of normal ATM. Cyclin G is found in the nucleus (Smith et al, 1997;Shimizu et al, 1998), and it binds to p53 and Mdm2 (Kimura et al, 2001;Chen, 2002;Okamoto et al, 2002;Ohtsuka et al, 2003). However, this nuclear localization of cyclin G is apparent only in normal fibroblast cells.…”

mentioning

confidence: 99%

“…Although the structural and biochemical aspects of cyclin G have been well established, the biological and functional relevance of cyclin G in a cellular context remains elusive. A number of studies have speculated on the possible cellular roles of the cyclin G protein, and these studies imply that cyclin G plays an essential role in cell cycle checkpoint control in response to DNA damage through the p53-Mdm2 network, and cyclin G may also have the potential to exert oncogenic properties (Kimura et al, 2001;Chen, 2002;Okamoto et al, 2002;Jensen et al, 2003;Ohtsuka et al, 2003). Our present study demonstrates that cyclin G plays an important role in regulating p53 function and in modulating the cellular response to DNA damage in an ATM kinase-dependent manner.…”

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confidence: 99%

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The negative role of cyclin G in ATM-dependent p53 activation

et al. 2004

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Cyclin G is one of the earliest p53 target genes to be identified, but its function in the p53 pathway has been elusive. Although the precise mechanisms of cyclin G in this novel network have not been explored, recent studies have demonstrated that cyclin G is a key regulator of the p53-Mdm2 network. Here we present evidence that cyclin G-mediated p53 regulation is dependent upon the status of ataxia-telangiectasia mutated (ATM) protein, which activates p53 in response to DNA damage. Abrogation of cyclin G enhances p53 accumulation and phosphorylation of p53 at the Ser-15 residue, resulting in cell cycle arrest. Ectopically expressed cyclin G significantly reduces the steady-state levels of p53 as well as that of phosphorylated p53 at Ser-15 after DNA damage in normal human dermal fibroblasts containing normal ATM. However, cyclin G does not cause similar reductions in p53 levels in ATM-mutated cells. We also show that translocation of cyclin G to the nucleus requires functional ATM. Thus, our findings identify a new role of cyclin G in ATM-dependent p53 regulation and in cell cycle regulation during DNA damage.

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supporting

confidence: 80%

mentioning

confidence: 84%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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The negative role of cyclin G in ATM-dependent p53 activation

et al. 2004

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Widespread tissue hypoxia dysregulates cell and metabolic pathways in SMA

Hernandez‐Gerez

Dall’Angelo

Collinson

et al. 2020

Ann Clin Transl Neurol

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Objective The purpose of the study was to determine the extent and role of systemic hypoxia in the pathogenesis of spinal muscular atrophy (SMA). Methods Hypoxia was assayed in vivo in early‐symptomatic (postnatal day 5) SMA‐model mice by pimonidazole and [18F]‐Fluoroazomycin arabinoside injections, which accumulate in hypoxic cells, followed by immunohistochemistry and tracer biodistribution evaluation. Glucose uptake in hypoxic cells was assayed by [18F]‐Fluorodeoxyglucose labeling. In vitro knockdown of Survival Motor Neuron (SMN) was performed on motor neurons and lactate metabolism measured biochemically, whereas cell cycle progression and cell death were assayed by flow cytometry. Results All assays found significant levels of hypoxia in multiple organ systems in early symptomatic SMA mouse pups, except aerated tissues such as skin and lungs. This was accompanied by significantly increased glucose uptake in many affected organs, consistent with a metabolic hypoxia response. SMN protein levels were shown to vary widely between motor neuron precursors in vitro, and those with lower levels were most susceptible to cell death. In addition, SMA‐model motor neurons were particularly sensitive to hypoxia, with reduced ability to transport lactate out of the cell in hypoxic culture, and a failure in normal cell cycle progression. Interpretation Not only is there widespread tissue hypoxia and multi‐organ cellular hypoxic response in SMA model mice, but SMA‐model motor neurons are especially susceptible to that hypoxia. The data support the hypothesis that vascular defects leading to hypoxia are a significant contributor to disease progression in SMA, and offer a route for combinatorial, non‐SMN related therapy.

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