Abstract
We have generated stable IIC9 cell lines, Goa1 and Goa2, that overexpress full-length antisense Goalpha RNA. As shown previously, expression of antisense Goalpha RNA ablated the alpha subunit of the heterotrimeric G protein, Go, resulting in growth in the absence of mitogen. To better understand this change in IIC9 phenotype, we have characterized the signaling pathway and cell cycle events previously shown to be important in control of IIC9 G1/S phase progression. In this paper we clearly demonstrate that ablation of Goalpha results in growth, constitutively active Ras/ERK, elevated expression of cyclin D1, and constitutively active cyclin D1-CDK complexes, all in the absence of mitogen. Furthermore, these characteristics were abolished by the transient overexpression of the transducin heterotrimeric G protein alpha subunit strongly suggesting the transformation of Goalpha-ablated cells involves Gobetagamma subunits. This is the first study to implicate a heterotrimeric G protein in tumor suppression.
Highlights
In IIC9 cells, a subclone of Chinese hamster embryo fibroblasts, platelet-derived growth factor (PDGF)1 is a potent mitogen (1)
In this paper we clearly demonstrate that ablation of Goa results in growth, constitutively active Ras/ERK, elevated expression of cyclin D1, and constitutively active cyclin D1-CDK complexes, all in the absence of mitogen
PDGF stimulates an increase in cyclin D1 expression concomitant with an increase in cyclin D1-CDK activity (1)
Summary
In IIC9 cells, a subclone of Chinese hamster embryo fibroblasts, platelet-derived growth factor (PDGF)1 is a potent mitogen (1). Our data demonstrate that loss of Goa expression in IIC9 cells results in unregulated growth by constitutively activating the Ras/ERK pathway, a pathway we and others have shown positively regulates cyclin D1-CDK activity through the increased expression of cyclin D1. Ablation of Goa Results in the Mitogen-independent Activation of Ras—IIC9 cells overexpressing constitutively activated Ras form multiple foci when grown in soft agar and do not growth arrest when serum-depleted (data not shown).
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