| In the past, retinoid-mediated growth suppression has been attributed to the ability of ATRA to bind with its receptors in the nucleus, the RARs and RXRs, and enhance or repress expression of one or more protein targets. Our laboratory has identified Rb2/p130 to be one such protein. Levels of Rb2/p130 are increased 5--10 fold following ATRA treatment of the retinoid sensitive ovarian adenocarcinoma cell line CAOV3, but not the retinoid resistant SKOV3 adenocarcinoma cell line. We have also found that the level of PP2Ac becomes elevated following ATRA treatment of either the retinoid sensitive CAOV3 cells, or SKOV3 cells made sensitive to ATRA by over-expression of RARalpha and RXRbeta, but not parental ATRA resistant SKOV3 cells. Our data suggest that ATRA increases Rb2/p130 levels by inducing PP2A, an enzyme which can dephosphorylate residues on Rb2/p130 necessary for its degradation by the proteasome.; In other experiments, we have also found that treatment of CAOV3 cells with ATRA causes a 5--10 fold increase in the protein level of the cyclin dependent kinase inhibitor (CDKI) p27/Kip1. p27/Kip1 increase in CAOV3 cells is not due to increased transcription as mRNA levels stay constant throughout ATRA treatment. This increase in p27/Kip1 protein level appears to be due to a decrease in the SCF component protein SKP2. This protein is responsible for the ligation of ubiquitin to p27/Kip1 in preparation for degradation. We have also shown that the ATRA dependent increase in p27/kip1 protein in CAOV3 cells leads to a decrease in the kinase activities of cyclin dependent kinase 4 following ATRA treatment.; In conclusion we have determined that ATRA mediated growth suppression in CAOV3 cells involves multiple pathways, and is at least in part due to upregulation of both p27/Kip1 and Rb2/p130. |
