Oncogenic K-Ras promotes proliferation in quiescent intestinal stem cells

• Mutationally activated K-Ras promotes proliferation of intestinal stem cells.
• Mutationally activated K-Ras decreases label retention in quiescent intestinal stem cells.
• MEK activity is required for K-Ras to affect the proliferative kinetics of stem cells.
• Mutationally activated K-Ras promotes mucosal repair after injury.

K-Ras is a monomeric GTPase that controls cellular and tissue homeostasis. Prior studies demonstrated that mutationally activated K-Ras (K-RasG12D) signals through MEK to promote expansion and hyperproliferation of the highly mitotically active transit-amplifying cells (TACs) in the intestinal crypt. Its effect on normally quiescent stem cells was unknown, however. Here, we have used an H2B-Egfp transgenic system to demonstrate that K-RasG12D accelerates the proliferative kinetics of quiescent intestinal stem cells. As in the TAC compartment, the effect of mutant K-Ras on the quiescent stem cell is dependent upon activation of MEK. Mutant K-Ras is also able to increase self-renewal potential of intestinal stem cells following damage. These results demonstrate that mutant K-Ras can influence intestinal homeostasis on multiple levels.