Prostaglandin A2 blocks the activation of G1 phase cyclin-dependent kinase without altering mitogen-activated protein kinase stimulation.

Abstract Prostaglandin A (PGA) reversibly blocked the cell cycle progression of NIH 3T3 cells at G and G/M phase. When it was applied to cells synchronized in G or S phase, cells were blocked at G and G/M, respectively. The G/M blockage was transient. Microinjected oncogenic leucine 61 Ras protein could not override the PGA induced G blockage, nor could previous transformation with the v-raf oncogene. The serum-induced activation of mitogen-activated protein kinase was not inhibited by PGA treatment. These data suggest that PGA blocks cell cycle progression without interfering with the cytosolic proliferative signaling pathway. Combined microinjection of E2F-1 and DP-1 proteins or microinjected adenovirus E1A protein, however, could induce S phase in cells arrested in G by PGA, indicating that PGA does not directly inhibit the process of DNA synthesis. In quiescent cells, PGA blocked the normal hyperphosphorylation of the retinoblastoma susceptible gene product and the activation of cyclin-dependent kinase (CDK) 2 and CDK4, in response to serum stimulation. PGA treatment elevated the p21 protein expression level. These data indicate that PGA may arrest the cell cycle in G by interfering with the activation of G phase CDKs.