Antimitogenesis linked to regulation of Skp2 gene expression

Abstract

Prostacyclin has many effects in the vasculature; one of the less well understood is the ability to block cell cycle progression through G1 phase. We previously reported that the prostacyclin mimetic, cicaprost, selectively inhibits cyclin E-cyclin-dependent kinase-2 (Cdk2), and now we show that it acts by regulating the expression of Skp2, the F-box protein that targets p27Kip1 for ubiquitin-mediated proteolysis. First, we show that cicaprost prevents the late G1 phase down-regulation of p27 Kip1 and that the inhibitory effect of cicaprost on cyclin E-Cdk2 activity and S phase entry is eliminated by deleting p27Kip1. Levels of the closely related Cdk2 inhibitor, p21Cip1, are unaffected by cicaprost. Moreover, we show that cicaprost blocks the induction of Skp2 tuRNA and that ectopic expression of a Skp2 cDNA overrides the effect of cicaprost on p27Kip1 levels and S phase entry. Our data show that inhibition of F-box protein gene expression can underlie the effect of a potent antimitogen.