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Wee1
Wee1 is a tyrosine kinase that is a crucial component of the G2–M cell cycle checkpoint that prevents entry into mitosis in response to cellular DNA damage. Before mitosis, CDK1 is maintained in an inactive state by WEE1 through phosphorylation of CDK1 at tyrosine 15, and then CDK1 is phosphorylated at threonine 14 by myelin transcription factor (MYT1) [6–8]. Therefore, WEE1 acts as a negative regulator of entry into mitosis at the G2–M transition by protecting the nucleus from cyclin B complexed with CDK1 activated in the cytoplasm. The transcriptional synthesis and activity of WEE1 increases during S and G2 phases, and decreases at M phase when it is hyper-phosphorylated. As the cell approaches the G2–M transition, in the absence of substantive DNA damage, polo-like kinase 1 (PLK1) phosphorylates WEE1, which targets WEE1 for degradation via the ubiquitin ligase complex.
ATR phosphorylates and activates CHK1, which then phosphorylates WEE1 and CDC25C, thereby both activating WEE1 kinase activity and inactivating CDC25C phosphatase activity. Then, WEE1 phosphorylates and inactivates the CDK1–cyclin B complex on tyrosine 15, resulting in cell-cycle arrest in G2, allowing time for DNA repair. Inhibition of WEE1 kinase activity and removal of the G2–M checkpoint is an attractive strategy to drive cancer cells to enter into unscheduled mitosis and ultimately undergo cell death via mitotic catastrophe. Taken together, these support an important role for WEE1 in both DNA repair and the maintenance of genomic integrity, and that WEE1 may be a viable therapeutic target in cancer therapy.
References
1.Matheson CJ,et al. Trends Pharmacol Sci. 2016;37(10):872–881.
ATR phosphorylates and activates CHK1, which then phosphorylates WEE1 and CDC25C, thereby both activating WEE1 kinase activity and inactivating CDC25C phosphatase activity. Then, WEE1 phosphorylates and inactivates the CDK1–cyclin B complex on tyrosine 15, resulting in cell-cycle arrest in G2, allowing time for DNA repair. Inhibition of WEE1 kinase activity and removal of the G2–M checkpoint is an attractive strategy to drive cancer cells to enter into unscheduled mitosis and ultimately undergo cell death via mitotic catastrophe. Taken together, these support an important role for WEE1 in both DNA repair and the maintenance of genomic integrity, and that WEE1 may be a viable therapeutic target in cancer therapy.
References
1.Matheson CJ,et al. Trends Pharmacol Sci. 2016;37(10):872–881.
Cell Cycle/DNA Damage
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AChR(5)
Antifolate(8)
ATM/ATR(23)
Aurora Kinase(37)
CLK(15)
c-Myc(16)
DHFR(4)
DNA Alkylator(29)
DNA gyrase(7)
DNA Repair Protein(21)
DNA/RNA Synthesis(85)
DNA-PK(11)
GPR(19)
HDAC(111)
Hec1/Nek2(9)
Integrin(38)
LIM Kinase (LIMK)(4)
Mps1/TTK(1)
Nucleoside Antimetabolite/Analog(19)
Other Targets(2)
PARP(30)
PLK(11)
Potassium Channel(55)
RAD51(1)
Rho(5)
ROCK(13)
Telomerase(4)
Topoisomerase(40)
Wee1(2)