Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 32, Issue 11, Pages 2065-2082Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00092-12
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Funding
- National Institutes of Health [CA124533, CA126826, CA141029, CA140369, AA018863, CA122109, CAL117957]
- National Cancer Institute Intramural [ZIABC005561, ZIABC005562, ZIABC005708]
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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.
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