Negative Regulation of the Stability and Tumor Suppressor Function of Fbw7 by the Pin1 Prolyl Isomerase

Sang Hyun Min, Alan W. Lau, Tae Ho Lee, Hiroyuki Inuzuka, Shuo Wei, Pengyu Huang, Shavali Shaik, Daniel Yenhong Lee, Greg Finn, Martin Balastik, Chun Hau Chen, Manli Luo, Adriana E. Tron, James A. DeCaprio, Xiao Zhen Zhou, Wenyi Wei, Kun Ping Lu

Research output: Contribution to journalArticlepeer-review

117 Citations (Scopus)

Abstract

Fbw7 is the substrate recognition component of the Skp1-Cullin-F-box (SCF)-type E3 ligase complex and a well-characterized tumor suppressor that targets numerous oncoproteins for destruction. Genomic deletion or mutation of FBW7 has been frequently found in various types of human cancers; however, little is known about the upstream signaling pathway(s) governing Fbw7 stability and cellular functions. Here we report that Fbw7 protein destruction and tumor suppressor function are negatively regulated by the prolyl isomerase Pin1. Pin1 interacts with Fbw7 in a phoshorylation-dependent manner and promotes Fbw7 self-ubiquitination and protein degradation by disrupting Fbw7 dimerization. Consequently, overexpressing Pin1 reduces Fbw7 abundance and suppresses Fbw7's ability to inhibit proliferation and transformation. By contrast, depletion of Pin1 in cancer cells leads to elevated Fbw7 expression, which subsequently reduces Mcl-1 abundance, sensitizing cancer cells to Taxol. Thus, Pin1-mediated inhibition of Fbw7 contributes to oncogenesis, and Pin1 may be a promising drug target for anticancer therapy.

Original languageEnglish
Pages (from-to)771-783
Number of pages13
JournalMolecular Cell
Volume46
Issue number6
DOIs
Publication statusPublished - 2012 Jun 29
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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