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J. Biol. Chem., Vol. 269, Issue 40, 24602-24607, 10, 1994

Inhibition of p21ras activation blocks proliferation but not differentiation of interleukin-3-dependent myeloid cells

K Okuda, TJ Ernst and JD Griffin
Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts 02115.

Interleukin-3 (IL-3) induces proliferation of immature myeloid cells and mast cells and prevents programmed cell death (apoptosis) in vitro. These activities are exerted through binding of IL-3 to specific, high affinity receptors that then initiate a series of intracellular signaling events. Among the earliest of these signaling events in an IL- 3-dependent cell line such as 32Dcl3 are activation of one or more receptor-associated tyrosine kinases followed by activation of p21ras. In an effort to define the functional role of p21ras activation in mediating the effects of IL-3, we constructed a series of sublines of 32Dcl3 in which a dominant inhibitory mutant of Ha-ras (c-Ha-ras(Asn- 17)) was expressed under the control of a steroid-inducible promoter. Steroid treatment (dexamethasone, 1 microM) specifically induced c-Ha- ras(Asn-17) protein and mRNA and blocked IL-3-induced accumulation of p21ras-GTP in 32Dcl3/p21rasN17 cell lines, but not in control cells. Dexamethasone slightly inhibited IL-3-dependent proliferation of control 32Dcl3 cell lines (to 80% of maximum), but it completely blocked proliferation of 32Dcl3/p21rasN17 cell lines and induced cell cycle arrest in G0/G1. This proliferative block could be overcome by cotransfection with v-ras, and was reversible if dexamethasone was washed out. Cells arrested by c-Ha-ras(Asn-17) were viable in culture for > 2 weeks, despite their inability to proliferate. Notably, however, these cells remained dependent on IL-3 for viability and initiated apoptosis within 18 h of IL-3 deprivation. Finally, granulocyte colony-stimulating factor-induced differentiation of 32Dcl3/p21rasN17 cells to neutrophils was not affected by steroid- induced expression of c-Ha-ras(Asn-17) and did not require removal of IL-3. These results suggest that IL-3-induced proliferation and maintenance of cell viability are either initiated through separate signal transduction pathways or require different degrees of p21ras activation. Similarly, granulocyte colony-stimulating factor-induced neutrophil differentiation is not blocked by expression of c-Ha-ras(Asn- 17).
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