Peptidyl-Prolyl Isomerase Pin1 Markedly Enhances the Oncogenic Activity of the Rel Proteins in the NF-κB family

摘要

The peptidyl-prolyl isomerase Pin1 is frequently upregulated in human cancers in which Rel/NF-κB is constitutively activated but its role in these cancers remains to be determined, and evidence is still lacking to show that Pin1 contributes to cell transformation by Rel/NF-κB. Rel/NF-κB’s transcriptional and oncogenic activities are modulated by several post-translational modifications and co-regulatory proteins, and previous studies showed that cytokine treatment induces binding of Pin1 to the RelA subunit of NF-κB, thereby enhancing RelA’s nuclear localization and stability. Here we show that Pin1 associates with the Rel subunits of NF-κB that are implicated in leukemia/lymphomagenesis, and modulates their transcriptional and oncogenic activities. Pin1 markedly enhanced transformation of primary lymphocytes by the human c-Rel protein and also increased cell transformation by the potent viral Rel/NF-κB oncoprotein v-Rel, in contrast to a Pin1 mutant in the WW domain involved in interaction with NF-κB. Pin1 promoted nuclear accumulation of Rel proteins in absence of activating stimuli. Importantly, inhibition of Pin1 function with the small molecule inhibitor juglone or with Pin1-specific shRNA led to cytoplasmic relocalization of endogenous c-Rel in human lymphoma-derived cell lines, markedly interfered with lymphoma cell proliferation, and suppressed endogenous Rel/NF-κB-dependent gene expression. Together these results demonstrate that Pin1 is an important regulator of Rel/NF-κB’s transforming activity and suggest that Pin1 may be a potential therapeutic target in Rel/NF-κB-dependent leukemia/lymphomas.