title: Peroxisome proliferator-activated receptor β/δ cross talks with E2F and attenuates mitosis in HRAS-expressing cells.
abstract: The role of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) in Harvey sarcoma ras (Hras)-expressing cells was examined. Ligand activation of PPARβ/δ caused a negative selection with respect to cells expressing higher levels of the Hras oncogene by inducing a mitotic block. Mitosis-related genes that are predominantly regulated by E2F were induced to a higher level in HRAS-expressing Pparβ/δ-null keratinocytes compared to HRAS-expressing wild-type keratinocytes. Ligand-activated PPARβ/δ repressed expression of these genes by direct binding with p130/p107, facilitating nuclear translocation and increasing promoter recruitment of p130/p107. These results demonstrate a novel mechanism of PPARβ/δ cross talk with E2F signaling. Since cotreatment with a PPARβ/δ ligand and various mitosis inhibitors increases the efficacy of increasing G₂/M arrest, targeting PPARβ/δ in conjunction with mitosis inhibitors could become a suitable option for development of new multitarget strategies for inhibiting RAS-dependent tumorigenesis.
authors.affiliation: Department of Veterinary and Biomedical Sciences and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Bokai
authors.initials: B
authors.lastname: Zhu
authors.forename: Combiz
authors.initials: C
authors.lastname: Khozoie
authors.forename: Moses T
authors.initials: MT
authors.lastname: Bility
authors.forename: Christina H
authors.initials: CH
authors.lastname: Ferry
authors.forename: Nicholas
authors.initials: N
authors.lastname: Blazanin
authors.forename: Adam B
authors.initials: AB
authors.lastname: Glick
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D050704:E2F4 Transcription Factor / Q000378:metabolism*; D059565:G2 Phase Cell Cycle Checkpoints; D015603:Keratinocytes / Q000378:metabolism; D051379:Mice; D008938:Mitosis; D047494:PPAR delta / Q000378:metabolism*; D048068:PPAR-beta / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis* / Q000235:genetics; D020239:Receptor Cross-Talk; D015398:Signal Transduction
chemical_list: D050704:E2F4 Transcription Factor; D047494:PPAR delta; D048068:PPAR-beta; D016283:Proto-Oncogene Proteins p21(ras)