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Negative regulation of the stability and tumor suppressor function of Fbw7 by the Pin1 prolyl isomerase.

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.

Pubmed ID: 22608923


  • Min SH
  • Lau AW
  • Lee TH
  • Inuzuka H
  • Wei S
  • Huang P
  • Shaik S
  • Lee DY
  • Finn G
  • Balastik M
  • Chen CH
  • Luo M
  • Tron AE
  • Decaprio JA
  • Zhou XZ
  • Wei W
  • Lu KP


Molecular cell

Publication Data

June 29, 2012

Associated Grants

  • Agency: NCI NIH HHS, Id: CA081156-08
  • Agency: NIA NIH HHS, Id: K99AG033104
  • Agency: NIA NIH HHS, Id: R01 AG017870
  • Agency: NIA NIH HHS, Id: R01 AG017870-10
  • Agency: NCI NIH HHS, Id: R01 CA167677
  • Agency: NCI NIH HHS, Id: R01 CA167677-14
  • Agency: NIGMS NIH HHS, Id: R01 GM089763
  • Agency: NIGMS NIH HHS, Id: R01 GM089763-03
  • Agency: NIGMS NIH HHS, Id: R01 GM089763-04
  • Agency: NIA NIH HHS, Id: R01AG017870
  • Agency: NCI NIH HHS, Id: R01CA167677
  • Agency: NIGMS NIH HHS, Id: R01GM089763

Mesh Terms

  • Amino Acid Sequence
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • F-Box Proteins
  • Gene Expression Regulation
  • Genes, Tumor Suppressor
  • Humans
  • Molecular Sequence Data
  • Peptidylprolyl Isomerase
  • Ubiquitin-Protein Ligases
  • Ubiquitination