title: Negative regulation of the stability and tumor suppressor function of Fbw7 by the Pin1 prolyl isomerase.
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.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Min
authors.forename: Alan W
authors.initials: AW
authors.lastname: Lau
authors.forename: Tae Ho
authors.initials: TH
authors.lastname: Lee
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inuzuka
authors.forename: Shuo
authors.initials: S
authors.lastname: Wei
authors.forename: Pengyu
authors.initials: P
authors.lastname: Huang
authors.forename: Shavali
authors.initials: S
authors.lastname: Shaik
authors.forename: Daniel Yenhong
authors.initials: DY
authors.lastname: Lee
authors.forename: Greg
authors.initials: G
authors.lastname: Finn
authors.forename: Martin
authors.initials: M
authors.lastname: Balastik
authors.forename: Chun-Hau
authors.initials: CH
authors.lastname: Chen
authors.forename: Manli
authors.initials: M
authors.lastname: Luo
authors.forename: Adriana E
authors.initials: AE
authors.lastname: Tron
authors.forename: James A
authors.initials: JA
authors.lastname: Decaprio
authors.forename: Xiao Zhen
authors.initials: XZ
authors.lastname: Zhou
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wei
authors.forename: Kun Ping
authors.initials: KP
authors.lastname: Lu
mesh_terms: D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D044783:F-Box Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D008969:Molecular Sequence Data; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D044767:Ubiquitin-Protein Ligases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase