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Stabilization of the Ras Oncoprotein by the Insulin-like Growth Factor 1 Receptor during Anchorage-independent Growth¹

Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania 19107

R^- cells are 3T3 cells derived from mouse embryos with a targeted disruption of the type 1 insulin-like growth factor receptor (IGF-IR) genes. R^- cells are refractory to transformation by a variety of viral and cellular oncogenes, including an activated Ras. R^- cells stably transfected with an activated Ha-Ras (R^-Ras cells) fail to form colonies in soft agar. An IGF-IR truncated at residue 1245 cannot transform R^- cells, even when strongly overexpressed. However, the combination of the truncated IGF-IR and an activated Ras induces transformation of R^- cells. We show here that the Ras oncoprotein is rapidly degraded when R^-Ras cells are grown under anchorage-independent conditions and that signaling from the truncated IGF-IR stabilizes Ras. In monolayer cultures, Ras levels remain constant regardless of the presence or absence of IGF-IR signaling. These results directly explain why Ras cannot transform mouse embryo fibroblasts devoid of IGF-IR. They also suggest a more generalized, alternative mechanism for transformation by Ras and, implicitly, another possible way for targeting Ras in tumor cells.

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