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13
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, 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 G
13, 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
G
13 transcript in transfected cells, in addition to the
6-kilobase pair endogenous mRNA. The transfection resulted in a
doubling of the expression of G
13 protein in these cells
as assessed by Western blot analysis. The transforming ability of the
mutant G
13 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
G
13-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 G
13 caused a further
increase in colony formation (117-153 colonies) in three of five
clones analyzed. Apparently G
13 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 G
13 expression.
These results demonstrate that G
13 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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