Volume 272, Number 47, Issue of November 21, 1997 pp. 29438-29441
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

COMMUNICATION:
The Constitutively Active Mutant G₁₃ Transforms Mouse Fibroblast Cells Deficient in Insulin-like Growth Factor-I Receptor

(Received for publication, March 13, 1997, and in revised form, October 12, 1997)

From the Section on Cellular and Molecular Physiology, Diabetes Branch, NIDDK and the ^§ Laboratory of Cellular Development and Oncology, NIDR, National Institutes of Health, Bethesda, Maryland 20892

Insulin-like growth factor-I (IGF-I) receptor plays an important role in normal cell cycle progression and tumor growth, and it is thought to be essential for cellular transformation. To test this hypothesis, we stably transfected a GTPase-deficient mutant human G₁₃, which is highly oncogenic when overexpressed in vitro, into R fibroblasts derived from IGF-I receptor-deficient mice. Northern blots of multiple clones revealed the expression of a 1.8-kilobase pair mutant G₁₃ transcript in transfected cells, in addition to the 6-kilobase pair endogenous mRNA. The transfection resulted in a doubling of the expression of G₁₃ protein in these cells as assessed by Western blot analysis. The transforming ability of the mutant G₁₃ was tested using the soft agar assay. Nontransfected R cells cultured with 10% fetal bovine serum failed to form colonies after 3 weeks. Most of the mutant G₁₃-expressing clones formed significant numbers of colonies (11-50 colonies/1000 cells plated). Overexpression of the IGF-I receptor enabled R cells to form colonies (27 colonies), and co-transfection of the mutant G₁₃ caused a further increase in colony formation (117-153 colonies) in three of five clones analyzed. Apparently G₁₃ works through pathways other than mitogen-activated protein kinase and c-Jun N-terminal kinase in transforming R cells, because their activities were not significantly altered by the mutant G₁₃ expression. These results demonstrate that G₁₃ can induce cellular transformation through pathways apparently independent of the IGF-I receptor and that activation of the IGF-I receptor signaling pathways, although not essential for the transforming phenotype, enhances the effect of other pathways.

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