PROSTAGLANDIN A(2) BLOCKS THE ACTIVATION OF G(1) PHASE CYCLIN-DEPENDENT KINASE WITHOUT ALTERING MITOGEN-ACTIVATED PROTEIN-KINASE STIMULATION

Prostaglandin A(2) (PGA(2)) reversibly blocked the cell cycle progress ion of NIH 3T3 cells at G(1) and G(2)/M phase, When it was applied to cells synchronized in G(0) or S phase, cells were blocked at G(1) and G(2)/M, respectively, The G(2)/M blockage was transient, Microinjected oncogenic leucine 61 Ras protein could not override the PGA(2) induce d G(1) blockage, nor could previous transformation with the v-raf onco gene, The serum-induced activation of mitogen-activated protein kinase was not inhibited by PGA(2) treatment, These data suggest that PGA(2) 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(1) by PGA(2), indicating that PG A(2) does not directly inhibit the process of DNA synthesis, In quiesc ent cells, PGA(2) blocked the normal hyperphosphorylation of the retin oblastoma susceptible gene product and the activation of cyclin-depend ent kinase (CDK) 2 and CDK4, in response to serum stimulation, PGA(2) treatment elevated the p21(Waf1/Cip1/Sdi1) protein expression level, T hese data indicate that PGA(2) may arrest the cell cycle in G(1) by in terfering with the activation of G(1) phase CDKs.