The regulatory β-subunit of protein kinase CK2 accelerates the degradation of CDC25A phosphatase through the checkpoint kinase Chk1

Abstract

Human CDC25 phosphatases play an important role in cell cycle regulation by removing inhibitory phosphate groups on cyclin-CDKs. Chk1 has been shown to phosphorylate CDC25 family members down-regulating their phosphatase activity through distinct mechanisms. The kinase activity of Chk1 is evident in unperturbed cells and becomes enhanced in response to DNA damage or stalled replication. We have previously shown that the activity of Chk1 is increased following interaction with the regulatory ß-subunit of protein kinase CK2. In the present study, ectopic expression of CK2ß during normal cell cycle progression is shown to enhance CDC25A degradation, and this occurs in a manner similar to that by which CDC25A is down-regulated upon activation of cellular checkpoint responses. By using RNA interference to specifically deplete cells of Chk1, we demonstrate that Chk1 mediates the down-regulation of endogenous CDC25A, which occurs upon induction of CK2ß expression. When degradation of CDC25A is induced by CK2ß during activation of the G2 checkpoint, it leads to partial dephosphorylation of Cdc2 at its inhibitory residue Tyr15. These results suggest that protein kinase CK2 is involved in cell cycle regulation and indicate the mechanism by which CDC25A turnover might be regulated by Chk1 in the absence of DNA damage.

CK2β Regulates Hematopoietic Stem Cell Biology and Erythropoiesis

“…We discovered that CK2β ‐deficient HSCs are expanded, due to a higher proliferation rate, but at the same time an amount of these cells undergoes apoptosis (Figure 2). This is in line with our previous findings in leukemia stem cells 23 and other studies that demonstrate the importance of CK2 in sustaining cell viability and the quite different roles of the 2 CK2 subunits in the control of cell cycle: while CK2α is more associated to cell cycle progression, 78–80 free CK2β is also involved in cell cycle inhibition in particular in the regulation of the checkpoint between G2/M phases 81 , 82 . Moreover, HSPCs exhibited alterations in the expression of transcription factors important for the maintenance of stemness properties as well as for lineage commitment 40 , 42 , 44 , 46 , 47 (Figure 2H).…”

“…This is in line with our previous findings in leukemia stem cells 23 and other studies that demonstrate the importance of CK2 in sustaining cell viability and the quite different roles of the 2 CK2 subunits in the control of cell cycle: while CK2α is more associated to cell cycle progression, 78–80 free CK2β is also involved in cell cycle inhibition in particular in the regulation of the checkpoint between G2/M phases. 81,82 Moreover, HSPCs exhibited alterations in the expression of transcription factors important for the maintenance of stemness properties as well as for lineage commitment 40,42,44,46,47 (Figure 2H). Thus, a combination of different problems such as the unbalanced expression of these factors, the higher mitotic rate, and reduced cell viability could lead to the loss of quiescence and subsequent exhaustion of HSPC pools coupled with reduction of their differentiation potential.…”

“…between G2/M phases. 81,82 Moreover, HSPCs exhibited alterations in the expression of transcription factors important for the maintenance of stemness properties as well as for lineage commitment 40,42,44,46,47 (Figure 2H). Thus, a combination of different problems such as the unbalanced expression of these factors, the higher mitotic rate, and reduced cell viability could lead to the loss of quiescence and subsequent exhaustion of HSPC pools coupled with reduction of their differentiation potential.…”