Cabrera E, Raninga P, Khanna KK, Freire R

: Claspin is essential for activating the DNA damage checkpoint effector kinase Chk1, a target in oncotherapy. Claspin functions are tightly correlated to Claspin protein stability, regulated by ubiquitin-dependent proteasomal degradation. Here we identify Glycogen Synthase Kinase 3-? (GSK3-?) as a new regulator of Claspin stability. Interestingly, as Chk1, GSK3-? ...

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is a therapeutic target in cancer. GSK3-? inhibition or knockdown stabilizes Claspin, whereas a GSK3-? constitutively active form reduces Claspin protein levels by ubiquitination and proteasome-mediated degradation. Our results also suggest that GSK3-? modulates the interaction of Claspin with ?-TrCP, a critical E3 ubiquitin ligase that regulates Claspin stability. Importantly, GSK3-? knock down increases Chk1 activation in response to DNA damage in a Claspin-dependent manner. Therefore, Chk1 activation could be a pro-survival mechanism that becomes activated upon GSK3-? inhibition. Importantly, treating triple negative breast cancer cell lines with Chk1 or GSK3-? inhibitors alone or in combination, demonstrates that Chk1/GSK3-? double inhibition restrains cell growth and triggers more apoptosis compared to individual treatments, thereby revealing novel possibilities for a combination therapy for cancer.

Date: Jul. 29, 2019

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