Defective K-Ras Oncoproteins Initiate Cancer In Vivo and Evolve to Overcome Impaired Effector Binding

ABSTRACT: The oncogenic proteins expressed in human cancer cells are exceedingly difficult targets for drug discovery due to intrinsic properties of the Ras GTPase switch. As a result, recent efforts have largely focused on inhibiting Ras-regulated kinase effector cascades, particularly the Raf/MEK/ERK and PI3 kinase/Akt/mTOR pathways. We constructed murine stem cell leukemia virus (MSCV) vectors encoding oncogenic K-RasD12 with additional “second site” amino acid substitutions that that impair PI3 kinase/Akt or Raf/MEK/ERK activation and performed bone marrow transduction/transplantation experiments in mice. In spite of attenuated signaling properties, defective K-Ras oncoproteins induced aggressive clonal T lineage acute lymphoblastic leukemia (T-ALL). These leukemias exhibited a high frequency of

ORGANISM(S): Mus musculus

SUBMITTER: Ashley Ward 

PROVIDER: E-GEOD-28687 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress