14-3-3γ mediates Cdc25A proteolysis to block premature mitotic entry after DNA damage

Kasahara, Kousuke; Goto, Hidemasa; Enomoto, Mika; Tomono, Yasuko; Kiyono, Tohru; Inagaki, Masaki

doi:10.1038/emboj.2010.157

Cited by 90 publications

(115 citation statements)

References 41 publications

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“…2 and Table I). Since ATR-mediated phosphorylation induces Chk1 autophosphorylation (the most likely direct trigger to spread Chk1 signals over nucleus) (Kasahara et al, 2010), this model fits with the observation that Ser345 phosphorylation triggers Chk1 release from the chromatin (Shimada et al, 2008;Smits et al, 2006;Zhang et al, 2005). Since important downstream effectors such as Cdc25A are distributed diffusely in the nucleus (Bekker-Jensen et al, 2006), the redistribution to the entire nucleus is essential for Chk1 to deliver checkpoint signals (Smits et al, 2006).…”

Section: Chk1 Autophosphorylation (Especially At Ser296)supporting

confidence: 50%

“…2) (Lu et al, 2005). Ser296-phosphorylated Chk1 is diffusely detected in the entire nucleus (nucleoplasm; soluble nuclear fraction), whereas Ser345-phosphorylated Chk1 is predominantly observed at DNA damage foci (Kasahara et al, 2010). These observations lead to a model in which this phosphorylation shift promotes the release of Chk1 from DNA damage foci on the chromatin (Fig.…”

Section: Chk1 Autophosphorylation (Especially At Ser296)mentioning

confidence: 92%

“…2) (Clarke and Clarke, 2005;Kasahara et al, 2010). After Chk1 autophosphorylation, ATR sites are rapidly dephosphorylated by phosphatases such as protein phosphatase 2A (PP2A) (Kasahara et al, 2010;LeungPineda et al, 2006) or PPM1D (also called Wip1 or PP2Cδ; Fig.…”

Section: Chk1 Autophosphorylation (Especially At Ser296)mentioning

confidence: 99%

“…Based on the localization of these proteins, ATR-induced Chk1 phosphorylation likely occurs at the sites of DNA damage on chromatin (Fig. 2) (Kasahara et al, 2010;Smits et al, 2006;Zhang et al, 2005).…”

Section: Chk1 Phosphorylation By Atrmentioning

confidence: 99%

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Novel Insights into Chk1 Regulation by Phosphorylation

Kasahara

Inagaki

2015

Cell Struct. Funct.

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ABSTRACT. Checkpoint kinase 1 (Chk1) is a conserved protein kinase central to the cell-cycle checkpoint during DNA damage response (DDR). Until recently, ATR, a protein kinase activated in response to DNA damage or stalled replication, has been considered as the sole regulator of Chk1. Recent progress, however, has led to the identification of additional protein kinases involved in Chk1 phosphorylation, affecting the subcellular localization and binding partners of Chk1. In fact, spatio-temporal regulation of Chk1 is of critical importance not only in the DDR but also in normal cell-cycle progression. In due course, many potent inhibitors targeted to Chk1 have been developed as anticancer agents and some of these inhibitors are currently in clinical trials. In this review, we summarize the current knowledge of Chk1 regulation by phosphorylation.

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Section: Chk1 Autophosphorylation (Especially At Ser296)supporting

confidence: 50%

Section: Chk1 Autophosphorylation (Especially At Ser296)mentioning

confidence: 92%

Section: Chk1 Autophosphorylation (Especially At Ser296)mentioning

confidence: 99%

Section: Chk1 Phosphorylation By Atrmentioning

confidence: 99%

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Novel Insights into Chk1 Regulation by Phosphorylation

Kasahara

Inagaki

2015

Cell Struct. Funct.

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“…The target sequence of 14-3-3␥, which was utilized in the previous study (36) is as follows; AAGAGCTATATCCTTAACCAT. H1299 cells were transfected with 40 nM (final concentration) of 14-3-3␥ siRNA or scrambled siRNA duplexes using siLentFect lipid reagent (Bio-Rad) and transfected once again 24 h later on.…”

Section: Methodsmentioning

confidence: 99%

14-3-3γ Inhibition of MDMX-mediated p21 Turnover Independent of p53

Lee

2011

Journal of Biological Chemistry

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The stability of p21, a cyclin-dependent kinase inhibitor, is highly regulated by various protein molecules through the cell cycle and in response to extracellular signals. One of the p21 regulators is MDMX, which can directly bind to p21 and mediate its proteasomal degradation in an ubiquitination-independent fashion. The fact that 14-3-3␥ binds to the MDMX domain adjacent to p21 binding suggests that this 14-3-3␥ may affect MDMX-mediated p21 proteasomal turnover. Indeed, we found that overexpression of 14-3-3␥ increased the level of both endogenous and exogenous p21 in p53-null cells by extending its half-life, leading to p21-dependent G1 arrest. Also, 14-3-3␥ excluded p21 from binding to MDMX in a dose-dependent manner as determined by co-immunroprecipitation in vitro using purified proteins and in cells. In response to DNA damage, the level of the 14-3-3␥-MDMX complex increased whereas that of the MDMX-p21 complex declined as detected by co-immunoprecipitation assays, leading to the induction of p21 in p53-null cells. Knockdown of 14-3-3␥ inversely alleviated the induction of p21 levels by DNA damage. Hence, our study as presented here unravels a new role for 14-3-3␥ in protecting p21 from MDMX-mediated proteasomal turnover, which may partially account for DNA damage-induced elevation of p21 levels independent of p53.

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The G2 checkpoint—a node‐based molecular switch

et al. 2017

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Tight regulation of the eukaryotic cell cycle is paramount to ensure genomic integrity throughout life. Cell cycle checkpoints are present in each phase of the cell cycle and prevent cell cycle progression when genomic integrity is compromised. The G2 checkpoint is an intricate signaling network that regulates the progression of G2 to mitosis (M). We propose here a node‐based model of G2 checkpoint regulation, in which the action of the central CDK1–cyclin B1 node is determined by the concerted but opposing activities of the Wee1 and cell division control protein 25C (CDC25C) nodes. Phosphorylation of both Wee1 and CDC25C at specific sites determines their subcellular localization, driving them either toward activity within the nucleus or to the cytoplasm and subsequent ubiquitin‐mediated proteasomal degradation. In turn, this subcellular balance of the Wee1 and CDC25C nodes is directed by the action of the PLK1 and CHK1 nodes via what we have termed the ‘nuclear and cytoplasmic decision states’ of Wee1 and CDC25C. The proposed node‐based model provides an intelligible structure of the complex interactions that govern the decision to delay or continue G2/M progression. The model may also aid in predicting the effects of agents that target these G2 checkpoint nodes.

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14-3-3γ mediates Cdc25A proteolysis to block premature mitotic entry after DNA damage

Cited by 90 publications

References 41 publications

Novel Insights into Chk1 Regulation by Phosphorylation

Novel Insights into Chk1 Regulation by Phosphorylation

14-3-3γ Inhibition of MDMX-mediated p21 Turnover Independent of p53

The G2 checkpoint—a node‐based molecular switch

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