Oncogenic K-Ras promotes proliferation in quiescent intestinal stem cells

Stem Cell Res. 2015 Jul;15(1):165-71. doi: 10.1016/j.scr.2015.06.003. Epub 2015 Jun 10.

Abstract

K-Ras is a monomeric GTPase that controls cellular and tissue homeostasis. Prior studies demonstrated that mutationally activated K-Ras (K-Ras(G12D)) 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-Ras(G12D) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Dextran Sulfate
  • Green Fluorescent Proteins / metabolism
  • Intestinal Mucosa / metabolism
  • Intestines / pathology*
  • Mice, Transgenic
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Stem Cells / metabolism
  • Stem Cells / pathology*

Substances

  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Dextran Sulfate
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)