ERK1 and ERK2 bind CIC-DUX4 to regulate its expression. (A) Diagram of how MAPK-ERK regulates CIC-DUX4 oncoprotein degradation. (B and C) Co-IP demonstrating ERK1 (B) and ERK2 (C) binding to HA-tagged CIC-DUX4. (D) Immunoblot of CIC (WT) null (H1975 M1) cells expressing HA-tagged CIC-DUX4, stimulated with EGF (100 ng/mL) for 6 h. (E) Immunoblot of CIC (WT) null (H1975 M1) cells expressing HA-tagged CIC-DUX4 treated with trametinib (1 μM) for 6 h. (F) Endogenous CIC-DUX4 expression in NCC_CDS_X1 cells treated with bortezomib (1 μM) for 6 h. (G) Co-IP of HA-tagged CIC-DUX4 and endogenous ubiquitin following treatment with EGF (100 ng/mL), bortezomib (proteasome inhibitor, 1 μM), and BCI (DUSP6 inhibitor, 1 μM) compared with no treatment in 293T cells.