Peroxisome Proliferator-Activated Receptor β/δ Cross Talks with E2F and Attenuates Mitosis in HRAS-Expressing Cells

The role of peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) in Harvey sarcoma ras (Hras)-expressing cells was examined. Ligand activation of PPARI beta/delta 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 Ppar beta/delta-null keratinocytes compared to HRAS-expressing wild-type keratinocytes. Ligand-activated PPAR beta/delta 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 PPAR beta/delta cross talk with E2F signaling. Since cotreatment with a PPAR beta/delta ligand and various mitosis inhibitors increases the efficacy of increasing G(2)/M arrest, targeting PPAR beta/delta in conjunction with mitosis inhibitors could become a suitable option for development of new multitarget strategies for inhibiting RAS-dependent tumorigenesis.