Journal
BLOOD
Volume 109, Issue 12, Pages 5238-5241Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2006-09-047050
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Funding
- NHLBI NIH HHS [P01 HL32262, P01 HL032262] Funding Source: Medline
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When overexpressed in primary erythroid progenitors, oncogenic Ras leads to the constitutive activation of its downstream signaling pathways, severe block of terminal erythrold 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 tetracyclineinducible 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 eff orts to modulate Ras signaling for treating hematopoietic malignancies.
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