Peroxisome proliferator-activated receptor ?/? cross talks with E2F and attenuates mitosis in HRAS-expressing cells.

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

SUBMITTER: Zhu B 

PROVIDER: S-EPMC3372236 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature