Figure 2 - K-Ras^G12D promotes hyperproliferation through Mek.

(a) Quantification of the number of Mcm6-positive cells at the bottom of the crypt shows that mutant K-Ras, but not mutant N-Ras, significantly increases the size of the progenitor cell population. ^*P < 0.01, Wilcoxon rank sum test. (b) The progenitor cells expressing K-Ras^G12D are hyperproliferative, as assessed by the number of cells per crypt that are positive for phosphorylated histone-H3, a marker of mitotic cells. ^*P < 0.01. (c) Inhibition of Mek with CI-1040 suppresses proliferation in colonic epithelium expressing mutant K-Ras. ^**P < 10^{- 24}, Wilcoxon rank sum test. Inhibition of Mek has no effect on proliferation in control colons. (d) Hematoxylin and eosin staining of normal, untreated colonic epithelium. (e) Hematoxylin and eosin staining of wild-type colon in an animal treated with CI-1040 for 24 h. (f) Hematoxylin and eosin staining of colonic epithelium expressing activated K-Ras^G12D showing crypt hyperplasia. (g) Hematoxylin and eosin staining of K-Ras^G12D colonic epithelium treated with CI-1040 for 24 h. Note the absence of hyperplasia and the return to somewhat normal histology. Scale bar in all panels, 50 m. Error bars, s.d.