The KSR1-ERK interaction is required for cell cycle reinitiation.
A, KSR1–/– or KSR1–/–
MEFs expressing KSR1, MEK-ERK, MEK-ERK+KSR1, or KSR1.AAAP were lysed and
subjected to Western blotting for the indicated proteins using an anti-KSR1
(top panel) or anti-ERK1/2 antibody (bottom two panels).
B, KSR1–/– or KSR1–/–
MEFs expressing either WT KSR1 or KSR1.AAAP were assessed for MMC-induced ERK
activation. MEFs were treated with 0.5 μg/ml MMC for 2 h, washed with PBS,
and incubated for the indicated times in fresh medium. Total and phospho-ERK
were assessed by Western blotting. C, KSR1–/–
MEFs expressing KSR1.AAAP were treated with 0.5 μg/ml MMC for 2 h
(light gray bars) or left untreated (dark gray bars).
Following MMC treatment, the cells were incubated with cytochalasin B for the
indicated times and analyzed by CBPI assay. The percentage of binucleated
cells is indicated. The values are the averages ± standard deviations
of three trials. Control KSR1–/– and
KSR1–/– MEFs expressing ectopic KSR1 are shown in
Fig. 2. D,
KSR1–/– MEFs expressing KSR1.AAAP were treated with MMC
(0.5 μg/ml) for 6 h and were analyzed by propidium iodide staining and flow
cytometry at the indicated times after treatment. The percent of cells in
G1 phase (black bars), S phase (gray bars), or
G2/M phases of the cell cycle (white bars) are shown. The
values are the averages ± standard deviations of three independent
trials. Control KSR1–/– and
KSR1–/– MEFs expressing ectopic KSR1 are shown in
Fig. 3. E,
KSR1–/– MEFs (diamonds) or
KSR1–/– MEFs expressing either KSR1 (squares),
MEK-ERK (triangles), or MEK-ERK+KSR1 (circles) were seeded
at 4 × 104 cells/35-mm-diameter dish. Triplicate dishes were
assessed for cell number every 48 h on a Beckman Coulter counter. Focus
formation assays were performed as described under “Experimental
Procedures.” Representative photomicrographs are shown (right
panel). F and G, KSR1–/– MEFs
expressing MEK-ERK or MEK-ERK+KSR1 were analyzed by CBPI assay (F) or
flow cytometry (G) as described above.