The gep oncogene, defined by the activated mutant of the α-subunit of the G protein G(12) (Gα(12)Q229L or Gα(12)QL), potently stimulates the proliferation of many different cell types in addition to inducing neoplastic transformation of several fibroblast cell lines. While it has been demonstrated that Gα(12)QL accelerates G1- to S-phase cell cycle progression, the precise mechanism through which Gα(12) communicates to cell cycle machinery is largely unknown. In the present study, we report that the activated-mutational as well as receptor-mediated-Gα(12) transmits its proliferative signals to cell cycle machinery by modulating the levels of the S-phase kinase-associated protein 2 (Skp2), an E3 ubiquitin ligase, involved in the regulation of the cyclin-dependent kinase inhibitor (CKI), p27(Kip1). Our results show that the expression of Gα(12)QL leads to an increase in the levels of Skp2 with a correlatable decrease in p27(Kip1) levels and subsequent increase in the activities of specific CDKs. By demonstrating that the transient expression of Gα(12)QL induces an increase in Skp2 levels with resultant downregulation of p27(Kip1) in both NIH3T3 and human astrocytoma 1321N1 cells, we establish here that the effect of Gα(12) on Skp2/p27(Kip1) is cell type independent. In addition, we demonstrate that LPA-stimulated proliferation and changes in Skp2 and p27(Kip1) levels in 1321N1 cells could be inhibited by the expression of a dominant-negative mutant of Gα(12), thereby pointing to the critical role of Gα(12) in LPA-mediated mitogenic signaling. Our findings also indicate that LPA as well as Gα(12)-mediated upregulation of Skp2 requires a yet to be characterized mechanism involving JNK. Since Skp2 has been identified as an oncogene, and it is overexpressed in many cancers, our results presented here describe for the first time that Skp2 is a novel target in the cell cycle machinery through which Gα(12) and its cognate receptors transmit their oncogenic signals.