Dae J Kim

Pennsylvania State University, University Park, MD, United States

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Publications (5)19.41 Total impact

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    ABSTRACT: Inhibition of cyclooxygenase-2 (COX2) by non-steroidal anti-inflammatory drugs (NSAID) is known to suppress skin carcinogenesis. It was further suggested that inhibition of COX2-derived prostaglandins by NSAIDs could reduce levels of putative endogenous ligands of peroxisome proliferator-activated receptor-beta (PPARbeta), and these ligands could potentiate tumorigenesis. However, it is currently unclear whether ligand activation of PPARbeta either inhibits or potentiates carcinogenesis. The present studies were designed to examine the mechanism of NSAID-mediated chemoprevention in skin, and, in particular, to determine the role of PPARbeta in this process. A two-stage skin carcinogenicity bioassay was performed using wild-type and PPARbeta-null mice that were fed either a control diet or one containing 0.32 g sulindac/kg diet. Significant inhibition of chemically induced skin carcinogenesis was observed in both wild-type and PPARbeta-null mice, and this was associated with a marked decrease in the concentration of skin prostaglandins including PGE(2) and PGI(2). Results from these studies demonstrate that inhibition of COX2 by dietary sulindac in mouse skin can effectively inhibit chemically induced skin carcinogenesis, and suggest that the mechanism underlying this chemopreventive effect is independent of PPARbeta. Additionally, results from these studies do not support the hypothesis that ligand activation of PPARbeta by COX-derived metabolites potentiates chemically induced skin carcinogenesis.
    Carcinogenesis 06/2006; 27(5):1105-12. · 5.64 Impact Factor
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    ABSTRACT: The physiological and pharmacological roles of peroxisome proliferator-activated receptor-beta (PPARbeta-also referred to as PPARdelta) are just beginning to emerge. It has recently become clear that PPARbeta has a function in epithelial tissues, but controversy exists due to inconsistencies in the literature. There is strong evidence that ligand activation of PPARbeta can induce terminal differentiation of keratinocytes, with a concomitant inhibition of cell proliferation. However, the role of PPARbeta in keratinocyte-specific apoptosis is less clear. Additionally, the role of PPARbeta in colonic epithelium remains unclear due to conflicting evidence suggesting that ligand activation of PPARbeta can potentiate, as well as attenuate, intestinal cancer. Recent studies revealed that ligand activation of PPARbeta can induce fatty acid catabolism in skeletal muscle and is associated with improved insulin sensitivity, attenuated weight gain and elevated HDL levels thus demonstrating promising potential for targeting PPARbeta for treating obesity, dyslipidemias and type 2 diabetes. Therefore, it becomes critical to determine the safety of PPARbeta ligands. This review focuses on recent literature describing the role of PPARbeta in epithelial tissues and highlights critical discrepancies that need to be resolved for a more comprehensive understanding of how this receptor modulates epithelial homeostasis.
    Cellular Signalling 02/2006; 18(1):9-20. · 4.47 Impact Factor
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    ABSTRACT: Recent work has shown that peroxisome proliferator-activated receptor beta (PPARbeta) attenuates cell proliferation and skin carcinogenesis, and this is due in part to regulation of ubiquitin C expression. In these studies, the role of PPARbeta in modulating ubiquitin-dependent protein kinase Calpha (PKCalpha) levels and phosphorylation signaling pathways was evaluated. Intracellular phosphorylation analysis showed that phosphorylated PKCalpha and other kinases were lower in wild-type mouse skin treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) as compared with PPARbeta-null mouse skin. No differences in expression levels of other PKC isoforms present in skin were observed. Lower ubiquitination of PKCalpha was found in TPA-treated PPARbeta-null skin as compared with wild-type, and inhibition of ubiquitin-dependent proteasome degradation prevented TPA-induced down-regulation of PKCalpha. The activity of PKCalpha and downstream signaling kinases is enhanced, and expression of cyclooxygenase-2 (COX-2) is significantly greater, in PPARbeta-null mouse skin in response to TPA compared with wild-type mouse skin. Inhibition of PKCalpha or COX-2 reduced cell proliferation in TPA-treated PPARbeta-null keratinocytes in a dose-dependent manner, whereas it only slightly influenced cell proliferation in wild-type keratinocytes. Combined, these studies provide strong evidence that PPARbeta attenuates cell proliferation by modulating PKCalpha/Raf1/MEK/ERK activity that may be due in part to reduced ubiquitin-dependent turnover of PKCalpha.
    Journal of Biological Chemistry 04/2005; 280(10):9519-27. · 4.65 Impact Factor
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    ABSTRACT: The role of peroxisome proliferator-activated receptor-beta (PPARbeta) in the molecular regulation of skin carcinogenesis was examined. Increased caspase-3 activity associated with apoptosis was found in the skin of wild-type mice after tumor promotion with 12-O-tetradecanoylphorbol-13-acetate, and this effect was diminished in PPARbeta-null mice. The onset of tumor formation, tumor size, and tumor multiplicity induced from a two-stage carcinogen bioassay (7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate) were significantly enhanced in PPARbeta-null mice compared with wild-type mice. To begin to characterize the molecular changes underlying this PPARbeta-dependent phenotype, microarray analysis was performed and a number of differentially regulated gene products were identified including ubiquitin C. Subsequent promoter analysis, reporter gene assays, site-directed mutagenesis, and electrophoretic mobility shift assays provide evidence that PPARbeta regulates ubiquitin C expression, and that ubiquitination of proteins is influenced by PPARbeta. These results strongly suggest that activation of PPARbeta-dependent target genes provides a novel strategy to inhibit tumor promotion and carcinogenesis.
    Journal of Biological Chemistry 06/2004; 279(22):23719-27. · 4.65 Impact Factor
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