Unscheduled CDK1 activity in G1 phase of the cell cycle triggers apoptosis in X-irradiated lymphocytic leukemia cells

Abstract

Cyclin-dependent kinase 1 (CDK1) is a major component of the cell cycle progression engine. Recently, several investigations provided evidence demonstrating that unscheduled CDK1 activation may also be involved in apoptosis in cancerous cells. In this article, we demonstrate that X-ray irradiation induced G1 arrest in MOLT-4 lymphocytic leukemia cells, the arrest being accompanied by reduction in the activity of CDK2, but increased CDK1 activity and cell apoptosis in the G1 phase. Interestingly, this increase in CDK1 and apoptosis by ionizing radiation was prevented by pretreatment with the CDK1 inhibitor, roscovitine, suggesting that CDK1 kinase activity is required for radiation-induced apoptotic cell death in this model system. Furthermore, cyclin B1 and CDK1 were detected co-localizing and associating in G1 phase MOLT-4 cells, with the cellular lysates from these cells revealing a genotoxic stress-induced increase in CDK1 phosphorylation (Thr-161) and dephosphorylation (Tyr-15), as analyzed by postsorting immunoprecipitation and immunoblotting. Finally, X-irradiation was found to increase Bcl-2 phosphorylation in G1 phase cells. Taken together, these novel findings suggest that CDK1 is activated by unscheduled accumulation of cyclin B1 in G1 phase cells exposed to X-ray, and that CDK1 activation, at the wrong time and in the wrong phase, may directly or indirectly trigger a Bcl-2-dependent signaling pathway leading to apoptotic cell death in MOLT-4 cells.

Synergy between Auraptene, Ionizing Radiation, and Anticancer Drugs in Colon Adenocarcinoma Cells

“…Exposure of cells to ionizing radiation delays the normal progression of cell cycle, and significant arrest might occur in G 1 , S, or G 2 phases that reflect induction of cellular processes assisting the irradiated cell to repair induced damages (Iliakis et al, ). Similar to current results, many studies have indicated delay in G 1 phase of the cell cycle upon X‐ray exposure, for instance in human glioma, leukemia, and holangiocarcinoma cells (Li et al, ; Wu et al, ; Hemaltulin et al, ). It has also been reported that auraptene, in toxic concentrations, induced sub‐G 1 peak in the flow cytometry histogram of breast, gastric, and prostate cancer cells (Mousavi et al, ; Moon et al, ; Lee et al, ) and inhibited cell proliferation by down regulating several genes involved in cell cycle control such as cyclin D1 , E2F1 , CDC2, and UHRF1, which promote G 1 to S phase transition (Krishnan and Kleiner‐Hancock, ).…”

Timing of apoptosis onset depends on cell cycle progression in peripheral blood lymphocytes and lymphocytic leukemia cells

“…The progression of the cell cycle and the execution of apoptosis have been demonstrated to be opposing processes (31)(32)(33). We found that the unscheduled activation of cyclin-dependent protein kinase 1 (CDK1/CDC2) was involved in the execution stage of apoptosis in MOLT-4 cells induced by X-ray irradiation (17). Others have shown that sublethal damage leading to a small quantity of caspase activation can protect neurons from more severe damage (34).…”

“…The phase specificity of apoptosis might represent the point at which the accumulated cell damage overwhelms the driving force for proliferation in a cell, and the cell consequently enters apoptosis. This implies that, at this point, the cell cycle machinery and the apoptotic process are acting at cross purposes (17).…”

Cell Cycle Regulators Guide Mitochondrial Activity in Radiation-Induced Adaptive Response

“…Cyclin B1/CDK1 is known to be responsible for initiating mitochondria-mediated apoptosis under cell damage conditions by phosphorylation of several pro-and antiapoptotic proteins (37, 219,229). CDK activity is involved in the mitochondrial translocation of Bax, which plays an important role in the mitochondrial membrane permeability transition during apoptotic progression (47).…”