DNA Damage-Induced Activation of p53 by the Checkpoint Kinase Chk2

Hirao, Atsushi; Kong, Young‐Yun; Matsuoka, Satomi; Wakeham, Andrew; Ruland, Jürgen; Yoshida, Hiroki; Liu, Dou; Elledge, Stephen J.; Mak, Tak W.

doi:10.1126/science.287.5459.1824

Cited by 1,159 publications

(955 citation statements)

References 23 publications

Supporting

Mentioning

898

Contrasting

Unclassified

Order By: Relevance

“…Strikingly, knock down of Chk1 allowed the irradiated HCT15 cells to recover from G2 arrest about 12 h earlier than the control cells (Figure 4). These observations are consistent with results in other cell lines suggesting that Chk1 has a major role in determining the G2 arrest in response to ionizing IR in mammalian cells, with Chk2 having a modulating role on the length of the delay (Hirao et al, 2000;Xiao et al, 2003).…”

Section: Effects Of Wip1 Overexpression On the G2 Cell Cycle Checkpointssupporting

confidence: 92%

The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase

et al. 2006

View full text Add to dashboard Cite

We previously demonstrated that type 2C protein phosphatases (PP2C) Ptc2 and Ptc3 are required for DNA checkpoint inactivation after DNA double-strand break repair or adaptation in Saccharomyces cerevisiae. Here, we show the conservation of this pathway in mammalian cells. In response to DNA damage, ataxia telangiectasia mutated (ATM) phosphorylates the Chk2 tumour suppressor kinase at threonine 68 (Thr68), allowing Chk2 kinase dimerization and activation by autophosphorylations in the T-loop. The oncogenic protein Wip1, a PP2C phosphatase, binds Chk2 and dephosphorylates phosphoThr68. Consequently, Wip1 opposes Chk2 activation by ATM after ionizing irradiation of cells. In HCT15 colorectal cancer cells corrected for functional Chk2 activity, Wip1 overexpression suppressed the contribution of Chk2 to the G2/M DNA damage checkpoint. These results indicate that Wip1 is one of the phosphatases regulating the activity of Chk2 in response to DNA damage.

show abstract

Section: Effects Of Wip1 Overexpression On the G2 Cell Cycle Checkpointssupporting

confidence: 92%

The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Especially, Chk2 is required for preservation, but not start, of G2 phase arrest induced by DNA damage. Chk2 was shown to synergize with other genes or factors that perpetuate DNA damage repair during G2/M phase rather than inducing G2/M phase arrest (Hirao et al 2000). Active Chk2 is known to phosphorylate ser-216 (negative regulatory site) of Cdc25C protein phosphatase, leading in turn to the inhibition of Cdc2 kinase and consequently G2/M blockade (Kastan and Bartek 2004;Niida and Nakanishi 2005).…”

Section: Discussionmentioning

confidence: 99%

Genistein-induced G2/M cell cycle arrest of human intestinal colon cancer Caco-2 cells is associated with Cyclin B1 and Chk2 down-regulation

2013

View full text Add to dashboard Cite

Genistein is an isoflavonic phyto-oestrogen contained in soya beans. It is thought to display anti-cancer effects. This study was designed to investigate its effect on human intestinal colon cancer Caco-2 cells. MTT assay, flow cytometric analysis and western blotting were used to investigate the effect of genistein on cell proliferation, cell cycle progression and protein alterations of selected cell cycle-related proteins in Caco-2 cells. Our results showed that genistein and daidzein significantly suppressed cell proliferation. Genistein treatment was demonstrated to modulate cell cycle distribution through accumulation of cells at G2/M phase, with a significant decreasing effect of Cyclin B1 and Serine/threonine-protein kinase 2 (Chk2) proteins expression. However, daidzein did not alter the cell cycle progression in Caco-2 cells. All these observation strongly indicate that genistein has anti-proliferative effect in human intestinal colon cancer Caco-2 cells through the downregulation of cell cycle check point proteins, Cyclin B1 and Chk2.

show abstract

“…Other factors, which have been defined as regulators of p53 posttranslational modifications and activation, include Chk2 and ATM. 24,30,31 By using HCT116 Chk2 À / À cells and a specific inhibitor of ATM (KU55933), we could conclude that these factors did not contribute significantly to any of the 5-FU-induced p53 phosphorylation events analyzed. Still, in Chk2 À / À cells, processing of caspases-3 and -8 occurred at a slower rate compared with the parental cell line, implicating this factor in 5-FU-induced apoptosis by a yet unknown mechanism (Figure 6c).…”

Section: Dr5mentioning

confidence: 91%

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

et al. 2012

View full text Add to dashboard Cite

5-Fluorouracil (5-FU) is an anti-metabolite that is in clinical use for treatment of several cancers. In cells, it is converted into three distinct fluoro-based nucleotide analogs, which interfere with DNA synthesis and repair, leading to genome impairment and, eventually, apoptotic cell death. Current knowledge states that in certain cell types, 5-FU-induced stress is signaling through a p53-dependent induction of tumor necrosis factor-receptor oligomerization required for death-inducing signaling complex formation and caspase-8 activation. Here we establish a role of calcium (Ca 2 þ ) as a messenger for p53 activation in response to 5-FU. Using a combination of pharmacological and genetic approaches, we show that treatment of colon carcinoma cells stimulates entry of extracellular Ca 2 þ through long lasting-type plasma membrane channels, which further directs posttranslational phosphorylation of at least three p53 serine residues (S15, S33 and S37) by means of calmodulin (CaM) activity. Obstructing this pathway by the Ca 2 þ -chelator BAPTA (1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid) or by inhibitors of CaM efficiently reduces 5-FUinduced caspase activities and subsequent cell death. Moreover, ectopic expression of p53 S15A in HCT116 p53 À / À cells confirmed the importance of a Ca 2 þ -CaM-p53 axis in 5-FU-induced extrinsic apoptosis. The fact that a widely used therapeutic drug, such as 5-FU, is operating via this pathway could provide new therapeutic intervention points, or specify new combinatorial treatment regimes.

show abstract

DNA Damage-Induced Activation of p53 by the Checkpoint Kinase Chk2

Cited by 1,159 publications

References 23 publications

The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase

The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase

Genistein-induced G2/M cell cycle arrest of human intestinal colon cancer Caco-2 cells is associated with Cyclin B1 and Chk2 down-regulation

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

Contact Info

Product

Resources

About