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Volume 272, Number 28, Issue of July 11, 1997 pp. 17312-17319
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Ablation of G_o -Subunit Results in a Transformed Phenotype and Constitutively Active Phosphatidylcholine-specific Phospholipase C

(Received for publication, February 4, 1997, and in revised form, April 30, 1997)

Jie Cheng , Jason D. Weber ^§ , Joseph J. Baldassare ^¶ and Daniel M. Raben

From the  Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 and the Departments of ^§ Cell and ^¶ Pharmacological and Physiological Sciences, St. Louis University School of Medicine, St. Louis, Missouri 63104

Modulation of the components involved in mitogenic signaling cascades is critical to the regulation of cell growth. GTP-binding proteins and the stimulation of phosphatidylcholine (PC) hydrolysis have been shown to play major roles in these cascades. One of the enzymes involved in PC hydrolysis, a PC-specific phospholipase C (PC-PLC) has received relatively little attention. In this paper we examined the role of a particular heterotrimeric GTP-binding protein, G_o, in the regulation of cell growth and PC-PLC-mediated hydrolysis of PC in IIC9 fibroblasts. The G_o -subunit was ablated in IIC9 cells by stable expression of antisense RNA. These stably transfected cells acquired a transformed phenotype as indicated by: (a) the formation of multiple foci in monolayer cultures, (b) the acquisition of anchorage-independent growth in soft agar; and (c) an increased level of thymidine incorporation in the absence of added mitogens. These data implicate G_o as a novel tumor suppressor. Interestingly, PC-PLC activity was constitutively active in the G_o-ablated cells as evidenced by the chronically elevated levels of diacylglycerol and phosphorylcholine in the absence of growth factors. In contrast, basal activities of PC-phospholipase D, phospholipase A₂, or phosphoinositol-PLC were not affected. These data demonstrate, for the first time, a role for G_o in regulating cell growth and provide definitive evidence for the existence of a PC-PLC in eukaryotic cells. The data further indicate that a subunit of G_o, is involved in regulating this enzyme.

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