title: Expression of oncogenic K-ras from its endogenous promoter leads to a partial block of erythroid differentiation and hyperactivation of cytokine-dependent signaling pathways.
abstract: When overexpressed in primary erythroid progenitors, oncogenic Ras leads to the constitutive activation of its downstream signaling pathways, severe block of terminal erythroid differentiation, and cytokine-independent growth of primary erythroid progenitors. However, whether high-level expression of oncogenic Ras is required for these phenotypes is unknown. To address this issue, we expressed oncogenic K-ras (K-ras(G12D)) from its endogenous promoter using a tetracycline-inducible system. We show that endogenous K-ras(G12D) leads to a partial block of terminal erythroid differentiation in vivo. In contrast to results obtained when oncogenic Ras was overexpressed from retroviral vectors, endogenous levels of K-ras(G12D) fail to constitutively activate but rather hyperactivate cytokine-dependent signaling pathways, including Stat5, Akt, and p44/42 MAPK, in primary erythroid progenitors. This explains previous observations that hematopoietic progenitors expressing endogenous K-ras(G12D) display hypersensitivity to cytokine stimulation in various colony assays. Our results support efforts to modulate Ras signaling for treating hematopoietic malignancies.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Yangang
authors.initials: Y
authors.lastname: Liu
authors.forename: Caroline
authors.initials: C
authors.lastname: Beard
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
authors.forename: Rudolf
authors.initials: R
authors.lastname: Jaenisch
authors.forename: Tyler E
authors.initials: TE
authors.lastname: Jacks
authors.forename: Harvey F
authors.initials: HF
authors.lastname: Lodish
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D016207:Cytokines / Q000494:pharmacology*; D004912:Erythrocytes / Q000166:cytology*; D004920:Erythropoiesis; D005786:Gene Expression Regulation; D051379:Mice; D008815:Mice, Inbred Strains; D015513:Oncogene Proteins; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects; D018631:ras Proteins / Q000235:genetics* / Q000502:physiology*
chemical_list: D016207:Cytokines; D015513:Oncogene Proteins; D018631:ras Proteins