ERK-1/-2 and p38 Kinase Oppositely Regulate 15-deoxy-delta(12,14)-prostaglandinJ2-Induced PPAR-gamma Activation That Mediates Dedifferentiation But Not Cyclooxygenase-2 Expression in Articular Chondrocytes

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a ligand-activated transcription factor and plays an important role in growth, differentiation, and inflammation in different tissues. In this study, we investigated the effects of 15d-PGJ2, a high-affinity ligand of PPAR-gamma, on dedifferentiation and on inflammatory responses such as COX-2 expression and PGE2 production in rabbit articular chondrocytes with a focus on ERK-1/-2, p38 kinase, and PPAR-gamma activation. We report here that 15d-PGJ2 induced dedifferentiation and/or COX-2 expression and subsequent PGE2 production. 15d-PGJ2 treatment stimulated activation of ERK-1/-2, p38 kinase, and PPAR-gamma. Inhibition of ERK-1/-2 with PD98059 recovered 15d-PGJ2-induced dedifferentiation and enhanced PPAR-gamma activation, whereas inhibition of p38 kinase with SB203580 potentiated dedifferentiation and partially blocked PPAR-gamma activation. Inhibition of ERK-1/-2 and p38 kinase abolished 15d-PGJ2-induced COX-2 expression and subsequent PGE2 production. Our findings collectively suggest that ERK-1/-2 and p38 kinase oppositely regulate 15d-PGJ2-induced dedifferentiation through a PPAR-gamma-dependent mechanism, whereas COX-2 expression and PGE2 production is regulated by ERK-1/-2 through a PPAR-gamma-independent mechanism but not p38 kinase in articular chondrocytes. Additionally, these data suggest that targeted modulation of the PPAR-gamma and mitogen-activated protein kinase pathway may offer a novel approach for therapeutic inhibition of joint tissue degradation.

Cell Cylce Regulatory Effects of Cyclic AMP in Cancer Cells Which Lack Wild-type p53 / 대한암학회지

PURPOSE: The activator of protein kinase A, cyclic AMP, has been a recognized growth inhibitor of certain cell types. The present study aimed to investigate the effects of dibutyryl cAMP on the growth of cancer cells which lack wild-type p53 and to determine the mechanism of growth inhibition. MATERIALS AND METHODS: Prostate and breast cancer cells were treated with dibutyryl cAMP and compared with untreated cells. Growth patterns of cells were assessed by trypan blue-excluding method and western blot was done to determine protein levels of cell cycle regulatory proteins which govern G1 and G1/S phase. Northern blot and immunoprecipitation were done to determine the level of mRNA of p21 and the association between cell cycle regulatory proteins. In vitro immune complex kinase assay was done to assess the activity of cdk2. RESULTS: cAMP reduced cell growth by 48 h. Cyclin D3 level was downregulated and RB protein level was decreased and mostly unphosphorylated forms remained. The association of RB with E2F1 was increased. While cdk2 levels remained constant throughout cAMP treatment, the activity of cdk2/cyclin E complex, which is responsible for entry into S phase, was downregulated. Cdk inhibitors, p27 and p21 were induced with cAMP treatment. CONCLUSION: These observation suggest that the growth inhibitory effects of dibutyryl cAMP on prostate and breast cancer cells were mediated by induction of cdk inhibitors such as p21 and p27 and RB activation in accordance with downregulation of cdk2.