Knockdown of Chk1, Wee1 and Myt1 by RNA Interference Abrogates G2 Checkpoint and Induces Apoptosis

Wang, Yuli; Decker, Stuart J.; Sebolt–Leopold, Judith S.

doi:10.4161/cbt.3.3.697

Cited by 124 publications

(103 citation statements)

References 46 publications

(53 reference statements)

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“…SS, supershift band as a complex of anti-myc antibody, KLF2 protein and oligos; S, shift band of KLF2-oligo complex; NS, nonspecific band (Figure 8b). Consistent with previous studies (Pendergast, 1996;Wang et al, 2004;Yuan et al, 2004), Wee1 expression markedly inhibited the percentage of apoptotic cells. It was observed that after MMS treatment, the percentage of apoptotic cells in Wee1-SKOV3 cells was 5.66% versus 9.35% in vector-only SKOV3 cells.…”

Section: Downregulation Of Wee1 By Klf2 Is Involved In Dna Damage-indsupporting

confidence: 80%

“…During cell cycle progression, M-phasepromoting factor (MPF), which is a complex of cdc2 and cyclin B, directly regulates the G2/M transition. The activated MPF is obligatory for entry into mitosis and is also required for DNA damage-induced apoptosis (Rowley et al, 1992;Tourret and McKeon, 1996;Elder et al, 2001;Li et al, 2002;Wang et al, 2004). Wee1 negatively regulates the MPF complex by phosphorylating cdc2 on a conserved tyrosine (Tyr15), which causes aberrant mitosis and resistance to DNA damageinduced apoptosis (Rowley et al, 1992;Tourret and McKeon, 1996;Elder et al, 2001;Li et al, 2002;Wang et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional repression of WEE1 by Kruppel-like factor 2 is involved in DNA damage-induced apoptosis

et al. 2005

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Human Kruppel-like factor 2 (KLF2) is a Cys 2 /His 2 zinc-finger-containing transcriptional factor, which is involved in multiple cellular pathways. Utilizing gene expression profiling to identify aberrantly expressed genes in ovarian cancer, we found that KLF2 was significantly and specifically downregulated in ovarian tumors. After reintroducing KLF2 into ovarian cancer cell lines, we observed decreased cell growth and increased sensitivity to DNA damage-induced apoptosis. Analysis of genes that could be potential targets of KLF2 revealed that KLF2 negatively regulated WEE1 expression. WEE1 encodes a tyrosine kinase that regulates the G2/M cell cycle transition. Expression of KLF2 markedly repressed the transcription of WEE1 by directly binding to an SP1/ CPBP motif located between À252 bp and the start codon of the WEE1 promoter. Both activation and zincfinger domains of KLF2 were required for this suppression of Wee1 expression. In addition, we demonstrated that Wee1 expression prevents cancer cells from undergoing apoptosis in response to DNA damage; however, this resistance was abolished by coexpression of KLF2, which inhibits WEE1 transcription. Thus, the level of WEE1 is regulated by KLF2 and enhanced KLF2 expression sensitizes cells to DNA damage-induced apoptosis.

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Section: Downregulation Of Wee1 By Klf2 Is Involved In Dna Damage-indsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Transcriptional repression of WEE1 by Kruppel-like factor 2 is involved in DNA damage-induced apoptosis

et al. 2005

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“…MYT1 negatively regulates CDC2/cyclin B1 by phosphorylation of Thr 14 and Tyr 15 and thus overexpression of MYT1 inhibits G 2 -M phase progression (44). RNA interferencetriggered down-regulation of MYT1 could abrogate DNA damage -induced G 2 arrest (45). Such a correlation remains to be shown in our setting.…”

Section: Discussionmentioning

confidence: 74%

213Bi-induced death of HSC45-M2 gastric cancer cells is characterized by G2 arrest and up-regulation of genes known to prevent apoptosis but induce necrosis and mitotic catastrophe

Seidl¹,

Port

Gilbertz

et al. 2007

Molecular Cancer Therapeutics

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Tumor cells are efficiently killed after incubation with A-emitter immunoconjugates targeting tumor-specific antigens. Therefore, application of A-emitter immunoconjugates is a promising therapeutic option for treatment of carcinomas that are characterized by dissemination of single tumor cells in the peritoneum like ovarian cancer or gastric cancer. In diffuse-type gastric cancer, 10% of patients express mutant d9-E-cadherin on the surface of tumor cells that is targeted by the monoclonal antibody d9MAb. Coupling of the A-emitter 213 Bi to d9MAb provides an efficient tool to eliminate HSC45-M2 gastric cancer cells expressing d9-E-cadherin in vitro and in vivo. Elucidation of the molecular mechanisms triggered by A-emitters in tumor cells could help to improve strategies of A-emitter radioimmunotherapy. For that purpose, gene expression of 213 Bi-treated tumor cells was quantified using a real time quantitative-PCR low-density array covering 380 genes in combination with analysis of cell proliferation and the mode of cell death. We could show that 213 Bi-induced cell death was initiated by G 2 arrest; up-regulation of tumor necrosis factor (TNF), SPHK1, STAT5A, p21, MYT1, and SSTR3; and down-regulation of SPP1, CDC25 phosphatases, and of genes involved in chromosome segregation. Together with morphologic changes, these results suggest that 213 Bi activates death cascades different from apoptosis. Furthermore, 213 Bitriggered up-regulation of SSTR3 could be exploited for improvement of the therapeutic regimen. [Mol Cancer Ther 2007;6(8):2346 -59]

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“…In addition, Chk1 and Chk2 may be associated with the occurrence of glioma (Sancer et al 2004). Moreover, previous studies reported that loss of Chk1 sensitizes tumor cells to many anticancer agents (Wang et al 2004;Sidi et al 2008;Monica et al 2008;Morgan et al 2010). All these above mentioned suggest the key role of Chk1 and Chk2 enzymes in the cell cycle checkpoints activation, which in turn promotes the DNA damage repairing (Bao et al 2006), thereby preventing the cells from radiation and chemical therapy associated death.…”

Section: Discussionmentioning

confidence: 99%

“…Chk1 and Chk2, two numbers of serine/threonine kinase of family, are key regulators in the DNA damage response (Zhou et al 2003;Kastan and Bartek 2004). Chk1 and Chk2 have been shown to be involved in multiple checkpoint pathways, including the S phase and G2/M phase regulating pathway (Zhou and Bartek 2004;Wang et al 2004). In addition, Chk1 and Chk2 may be associated with the occurrence of glioma (Sancer et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Checkpoint Kinase 1 Is Associated with the Increased Radiosensitivity of Glioblastoma Stem-Like Cells

Lai

Wan

et al. 2012

Tohoku J. Exp. Med.

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Glioblastoma multiforme is an aggressive brain tumor with a poor prognosis. The glioblastoma stem-like cells (GSCs) represent a rare fraction of human glioblastoma cells with the capacity for multi-lineage differentiation, self-renewal and exact recapitulation of the original tumor. Interestingly, GSCs are more radioresistant compared with other tumor cells. In addition, the remarkable radioresistance of GSCs has been known to promote radiotherapy failure and therefore is associated with a significantly higher risk of a local tumor recurrence. Moreover, the hyperactive cell cycle checkpoint kinase (Chk) 1 and 2 play a pivotal role in the DNA damage response including radiation and chemical therapy. Based on aforementioned, we hypothesized that knockdown of Chk1 or Chk2 might confer radiosensitivity on GSCs and thereby increases the efficiency of radiotherapy. In this study, we knocked down the expression of Chk1 or Chk2 in human GSCs using lentivirus-delivered short hairpin RNA (shRNA) to examine its effect on the radiosensitivity. After radiation, the apoptosis rate and the cell cycle of GSCs were measured with Flow Cytometry. Compared with control GSCs (apoptosis, 7.82 ± 0.38%; G2/M arrest, 60.20 ± 1.28%), Chk1 knockdown in GSCs increased the apoptosis rate (37.87 ± 0.32%) and decreased the degree of the G2/M arrest (22.37 ± 2.01%). In contrast, the radiosensitivity was not enhanced by Chk2 knockdown in GSCs. These results suggest that depletion of Chk1 may improve the radio-sensitivity of GSCs via inducing cell apoptosis. In summary, the therapy targeting Chk1 gene in the GSCs may be a novel way to treat glioblastoma.

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Knockdown of Chk1, Wee1 and Myt1 by RNA Interference Abrogates G2 Checkpoint and Induces Apoptosis

Cited by 124 publications

References 46 publications

Transcriptional repression of WEE1 by Kruppel-like factor 2 is involved in DNA damage-induced apoptosis

Transcriptional repression of WEE1 by Kruppel-like factor 2 is involved in DNA damage-induced apoptosis

213Bi-induced death of HSC45-M2 gastric cancer cells is characterized by G2 arrest and up-regulation of genes known to prevent apoptosis but induce necrosis and mitotic catastrophe

Knockdown of Checkpoint Kinase 1 Is Associated with the Increased Radiosensitivity of Glioblastoma Stem-Like Cells

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