Targeting the checkpoint kinase Chk1 in cancer therapy

Merry, Callie R.; Fu, Kang; Wang, Jingna; Yeh, I‐Ju; Zhang, Youwei

doi:10.4161/cc.9.2.10445

Cited by 72 publications

(57 citation statements)

References 49 publications

(46 reference statements)

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“…Although the role of Chk2 in G2 arrest has been contested (Ahn et al, 2003;Jallepalli et al, 2003;Jin et al, 2008), an everincreasing family of Chk1 targets (Dai and Grant, 2010) reinforces the notion that Chk1 is the major player of the DNA damage checkpoint and hence a promising target in combined anticancer therapy (Merry et al, 2010).…”

Section: Discussionmentioning

confidence: 84%

“…The mechanism of this feedback control is not known, but it could involve stabilization of Chk1 that is normally rapidly degraded by the proteasome (Zhang et al, 2005;Merry et al, 2010) or its increased expression (Gottifredi et al, 2001). Our finding that p21 depletion or impaired induction strongly stimulated Chk1 activation by DNA damage might explain why p53-or p21-deficient cells arrest temporarily in G2 (Levedakou et al, 1995;Bunz et al, 1998;Andreassen et al, 2001) and why Chk1 depletion promoted mitosis in g-irradiated p53-proficient U2OS cells (Syljuasen et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

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Chk1 is dispensable for G2 arrest in response to sustained DNA damage when the ATM/p53/p21 pathway is functional

Lossaint

Besnard²,

Fisher³

et al. 2011

Oncogene

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In the presence of sustained DNA damage occurring in S-phase or G2, normal cells arrest before mitosis and eventually become senescent. The checkpoint kinases Chk1/ Chk2 and the CDK inhibitor p21 are known to have important complementary roles in this process, in G2 arrest and cell cycle exit, respectively. However, additional checkpoint roles have been reported for these regulators and it is not clear to what extent their functions are redundant.Here we compared the respective roles of Chk1, Chk2 and p21 in DNA damage-induced G2 arrest in normal human fibroblasts, normal epithelial cells and frequently used p53 proficient cancer cells. We show that in normal cells, Chk1, but not Chk2, is involved in G2 arrest whereas neither are essential. In contrast, p21 is required. However, Chk1, but not Chk2, becomes necessary for arrest in U2OS osteosarcoma cells. We find that their ATM/p53/p21 response in G2 phase is defective, like in other cancer cells with wild-type p53, and conclude that cross-talk between the Chk1 and p21 pathways allows them to switch dependency for G2 arrest onto Chk1. Using the specific ATM inhibitor KU-55933 we confirm the essential role of ATM in the induction of p21 for G2 arrest of normal cells. Efficient p21 induction is required for nuclear sequestration of inactive cyclin B1-Cdk1 complexes preceding irreversible cell cycle exit in G2. Our results demonstrate that p21 is able to fulfill the Chk1 functions in G2 arrest under continuous genotoxic stress, which has important implications for cancer chemotherapy.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Chk1 is dispensable for G2 arrest in response to sustained DNA damage when the ATM/p53/p21 pathway is functional

Lossaint

Besnard²,

Fisher³

et al. 2011

Oncogene

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show abstract

“…11,34 Checkpoint kinases (Chk1 or Chk2) phosphorylate Cdc25 proteins, inactivating and keeping Cdc25 proteins out of the nucleus or by causing proteolytic degradation. 11,35 This causes G 1 /S or G 2 /M arrest in human cell lines, because unphosphorylated Cdc25 proteins dephosphorylate Cdk2 and Cdc2, the different results in our study on mouse oocytes.…”

Section: Discussionmentioning

confidence: 99%

Checkpoint kinase 1 is essential for meiotic cell cycle regulation in mouse oocytes

et al. 2012

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“…Accordingly, Chk1 inhibitors such as UCN-01 have been proposed for use in p53-deficient tumors under the assumption that combined p53 loss of function and Chk1 inhibition will preferentially allow damaged cancer cells to enter mitosis. [22][23][24] Out of the Frying Pan, into the Fire?…”

Section: Dual Control Of Mitotic Entry By Cdk2 and P53mentioning

confidence: 99%