title: Oncogenic K-Ras promotes proliferation in quiescent intestinal stem cells.
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.
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Gierut
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Lyons
authors.affiliation: Division of Endocrinology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
authors.forename: Manasvi S
authors.initials: MS
authors.lastname: Shah
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Casie
authors.initials: C
authors.lastname: Genetti
authors.affiliation: Division of Endocrinology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Breault
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA, USA. Electronic address: khaigis@bidmc.harvard.edu.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Haigis
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D016264:Dextran Sulfate; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology*; D008822:Mice, Transgenic; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D016264:Dextran Sulfate; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)