Drug Discov Ther. 2023;17(1):10-17. (DOI: 10.5582/ddt.2022.01120)

Redundant roles of extra-cellular signal-regulated kinase (ERK) 1 and 2 in the G1-S transition and etoposide-induced G2/M checkpoint in HCT116 cells

Erdenebaatar P, Gunarta IK, Suzuki R, Odongoo R, Fujii T, Fukunaga R, Kanemaki MT, Yoshioka K

The extracellular signal-regulated kinase (ERK) 1 and 2 intracellular signaling pathways play key roles in a variety of cellular processes, such as proliferation and differentiation. Dysregulation of ERK1/2 signaling has been implicated in many diseases, including cancer. Although ERK1/2 signaling pathways have been extensively studied, controversy remains as to whether ERK1 and ERK2 have specific or redundant functions. In this study, we examined the functional roles of ERK1 and ERK2 in cell proliferation and cell cycle progression using an auxin-inducible degron system combined with gene knockout technology. We found that ERK1/2 double depletion, but not ERK1 or ERK2 depletion, substantially inhibited the proliferation of HCT116 cells during G1-S transition. We further demonstrated that ERK1/2-double-depleted cells were much more tolerant to etoposide-induced G2/M arrest than ERK1 or ERK2 single-knockout cells. Together, these results strongly suggest the functional redundancy of ERK1 and ERK2 in both the G1-S transition under physiological conditions and the DNA damage-induced G2/M checkpoint. Our findings substantially advance understanding of the ERK1/2 pathways, which could have strong implications for future pharmacological developments.

Full Text: