title: Ligand activation of peroxisome proliferator-activated receptor-beta/delta(PPARbeta/delta) inhibits cell growth of human N/TERT-1 keratinocytes.
abstract: The functional role of peroxisome proliferator-activated receptor-beta(PPARbeta; also referred to as PPARdelta) in epidermal cell growth remains controversial. Recent evidence suggests that ligand activation of PPARbeta/delta increases cell growth and inhibits apoptosis in epidermal cells. In contrast, other reports suggest that ligand activation of PPARbeta/delta leads to the induction of terminal differentiation and inhibition of cell growth. In the present study, the effect of the highly specific PPARbeta/delta ligand GW0742 on cell growth was examined using a human keratinocyte cell line (N/TERT-1) and mouse primary keratinocytes. Ligand activation of PPARbeta/delta with GW0742 prevented cell cycle progression from G1 to S phase and attenuated cell proliferation in N/TERT-1 cells. Despite specifically activating PPARbeta/delta as revealed by target gene induction, no changes in PTEN, PDK and ILK expression or downstream phosphorylation of Akt were found in either N/TERT-1 cells or primary keratinocytes. Further, altered cell growth resulting from serum withdrawal and the induction of caspase-3 activity by ultraviolet radiation were unchanged in the absence of PPARbeta/delta expression and/or the presence of GW0742. While no changes in the expression of mRNAs encoding cell cycle control proteins were found in response to GW0742, a significant decrease in the level of ERK phosphorylation was observed. Results from these studies demonstrate that ligand activation of PPARbeta/delta does not lead to an anti-apoptotic effect in either human or mouse keratinocytes, but rather, leads to inhibition of cell growth likely through the induction of terminal differentiation.
authors.affiliation: Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Huck Institute of Life Sciences, The Pennsylvania State University, University Park 16802, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Burdick
authors.forename: Moses T
authors.initials: MT
authors.lastname: Bility
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Girroir
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Billin
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Willson
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology / Q000528:radiation effects; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D047494:PPAR delta / Q000378:metabolism*; D048068:PPAR-beta / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D015533:Transcriptional Activation; D014466:Ultraviolet Rays; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D018797:Cell Cycle Proteins; D008024:Ligands; D047494:PPAR delta; D048068:PPAR-beta; D051059:PTEN Phosphohydrolase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D019098:Telomerase; D013844:Thiazoles; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C509186:TERT protein, human