An Overactivated ATR/CHK1 Pathway Is Responsible for the Prolonged G2 Accumulation in Irradiated AT Cells

Wang, Xiang; Khadpe, Jay; Hu, Baocheng; Iliakis, George; Wang, Ya

doi:10.1074/jbc.m301876200

Cited by 69 publications

(67 citation statements)

References 57 publications

(64 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[50][51][52] In this study, we have shown that ATR and ATM kinase activity is high in exponentially growing ES cells in contrast to primary embryonic fibroblasts (Fig. 1B).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the ATR/Chk1 Pathway Induces a p38-Dependent S-phase Delay in Mouse ES Cells

Jirmanova

Bulavin²,

Fornace³

2005

Cell Cycle

View full text Add to dashboard Cite

“…[50][51][52] In this study, we have shown that ATR and ATM kinase activity is high in exponentially growing ES cells in contrast to primary embryonic fibroblasts (Fig. 1B).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the ATR/Chk1 Pathway Induces a p38-Dependent S-phase Delay in Mouse ES Cells

Jirmanova

Bulavin²,

Fornace³

2005

Cell Cycle

View full text Add to dashboard Cite

“…Prolongation of G 2 arrest after IR has been reported in AT cells and is known as "G 2 accumulation" (37). This phenomenon has been reported to occur due to overactivated ATR/Chk1 pathway in irradiated AT cells (6). Therefore, prolongation of IR-induced G 2 arrest in COX-2-overexpressing cells may be due to upregulated ATR by COX-2.…”

Section: Discussionmentioning

confidence: 95%

“…The deletion of the ATR gene causes early embryonic lethality in mice, and the mutation of this gene results in Seckel syndrome, which is characterized by a defective DNA damage response (10)(11)(12). Loss of ATR function also inhibits phosphorylation of downstream effectors such as p53 and Chk1 and leads to apoptosis (6,13). These facts indicate that ATR is essential for cell survival, development, and DNA damage response pathways (10,11).…”

Section: Introductionmentioning

confidence: 95%

“…They are cell cycle checkpoint kinases; in their active form, they inhibit the transition of cells with damaged DNA from G 2 into the mitotic (M) phase. They have sequential/structural homology and share the same substrates for specific DNA damage repair pathways (6)(7)(8)(9). Although ATM and ATR cross talk, they respond differently to genotoxic stresses.…”

Section: Introductionmentioning

confidence: 99%

“…When DNA is damaged, the ATM/checkpoint kinase 2 (Chk2) pathway is activated at an early time point, whereas activation of the ATR/Chk1 pathway occurs at a later stage (10,11). ATM/Chk2 responds primarily to DNA double strand breaks, whereas ATR/Chk1 is activated by DNA replication fork stalling and bulky DNA lesions (2,3,5,6,11). The deletion of the ATR gene causes early embryonic lethality in mice, and the mutation of this gene results in Seckel syndrome, which is characterized by a defective DNA damage response (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cyclooxygenase-2 Up-Regulates Ataxia Telangiectasia and Rad3 Related through Extracellular Signal-Regulated Kinase Activation

Kim

Lee

Park

et al. 2009

Molecular Cancer Research

View full text Add to dashboard Cite

Cyclooxygenase-2 (COX-2) overexpression caused prolonged G 2 arrest after exposure to ionizing radiation (IR) in our previous study. We were therefore interested in investigating the function of COX-2 in the G 2 checkpoint pathway. Interestingly, we found that cells in which COX-2 is overexpressed showed up-regulated ataxia telangiectasia and Rad3 related (ATR) expression compared with control cells. In this study, we investigated the mechanism of ATR up-regulation by COX-2 and tested our hypothesis that COX-2-induced extracellular signal-regulated kinase (ERK) activation mediates up-regulation of ATR by COX-2. To investigate the relationship between COX-2 and ATR, we used two stable COX-2-overexpressing cancer cell lines (HCT116-COX-2 and H460-COX-2), a COX-2 knockdown A549 lung cancer cell line (AS), and an ATR knockdown HCT116 cell line. Cells were treated with various drugs [celecoxib, prostaglandin E 2 (PGE 2 ), PD98059, U0126, and hydroxyurea] and were then analyzed using reverse transcription-PCR, confocal microscopy, Western blotting, and clonogenic assay. COX-2-overexpressing cells were shown to have increased ERK phosphorylation and ATR expression compared with control cells, whereas AS cells were shown to have decreased levels of phospho-ERK and ATR. In addition, exogenously administered PGE 2 increased ERK phosphorylation. Inhibition of ERK phosphorylation decreased ATR expression in both HCT116-COX-2 and A549 cells. HCT116-COX-2 cells were resistant to IR or hydroxyurea compared with HCT116-Mock cells, whereas administration of ATR shRNA showed the opposite effect. COX-2 stimulates ERK phosphorylation via PGE 2 . This COX-2-induced ERK activation seems to increase ATR expression and activity in endogenous COX-2-overexpressing cancer cells as well as in COX-2-overexpressing stable cell

show abstract

Upregulation of the ATR‐CHEK1 pathway in oral squamous cell carcinomas

Parikh

Appleman

Bauman

et al. 2013

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

The ATR-CHEK1 pathway is upregulated and overactivated in Ataxia Telangiectasia (AT) cells, which lack functional ATM protein. Loss of ATM in AT confers radiosensitivity, although ATR-CHEK1 pathway overactivation compensates, leads to prolonged G2 arrest after treatment with ionizing radiation (IR), and partially reverses the radiosensitivity. We observed similar upregulation of the ATR–CHEK1 pathway in a subset of oral squamous cell carcinoma (OSCC) cell lines with ATM loss. In the present study, we report copy number gain, amplification, or translocation of the ATR gene in 8 of 20 OSCC cell lines by FISH; whereas the CHEK1 gene showed copy number loss in 12 of 20 cell lines by FISH. Quantitative PCR showed overexpression of both ATR and CHEK1 in 7 of 11 representative OSCC cell lines. Inhibition of ATR or CHEK1 with their respective siRNAs resulted in increased sensitivity of OSCC cell lines to IR by the colony survival assay. siRNA-mediated ATR or CHEK1 knockdown led to loss of G2 cell cycle accumulation and an increased sub-G0 apoptotic cell population by flow cytometric analysis. In conclusion, the ATR-CHEK1 pathway is upregulated in a subset of OSCC with distal 11q loss and loss of the G1 phase cell cycle checkpoint. The upregulated ATR-CHEK1 pathway appears to protect OSCC cells from mitotic catastrophe by enhancing the G2 checkpoint. Knockdown of ATR and/or CHEK1 increases the sensitivity of OSCC cells to IR. These findings suggest that inhibition of the upregulated ATR–CHEK1 pathway may enhance the efficacy of ionizing radiation treatment of OSCC.

show abstract

An Overactivated ATR/CHK1 Pathway Is Responsible for the Prolonged G2 Accumulation in Irradiated AT Cells

Cited by 69 publications

References 57 publications

Inhibition of the ATR/Chk1 Pathway Induces a p38-Dependent S-phase Delay in Mouse ES Cells

Inhibition of the ATR/Chk1 Pathway Induces a p38-Dependent S-phase Delay in Mouse ES Cells

Cyclooxygenase-2 Up-Regulates Ataxia Telangiectasia and Rad3 Related through Extracellular Signal-Regulated Kinase Activation

Upregulation of the ATR‐CHEK1 pathway in oral squamous cell carcinomas

Contact Info

Product

Resources

About