The F-box protein FBX4 targets PIN2/TRF1 for ubiquitin-mediated degradation and regulates telomere maintenance.
Pin2/TRF1 was identified previously as both a protein (TRF1) that binds to telomeric DNA repeats and as a protein (Pin2) that associates with the kinase NIMA and suppresses its mitosis inducing activity. Pin2/TRF1 negatively regulates telomere length and also plays a critical role in cell cycle checkpoint control. Pin2/TRF1 is ... down-regulated in many human cancers and may be degraded by the ubiquitin-proteasome pathway, but components of the pathway involved in Pin2/TRF1 turnover have not been elucidated. By using the two-hybrid system, we recently identified Pin2/TRF1-interacting proteins, PinX1-4, and we demonstrated that PinX1 is a conserved telomerase inhibitor and a putative tumor suppressor. Here we report the characterization of PinX3. PinX3 was later found to be identical to Fbx4, a member of the F-box family of proteins, which function as substrate-specific adaptors of Cul1-based ubiquitin ligases. Fbx4 interacts with both Pin2 and TRF1 isoforms and promotes their ubiquitination in vitro and in vivo. Moreover, overexpression of Fbx4 reduces endogenous Pin2/TRF1 protein levels and causes progressive telomere elongation in human cells. In contrast, inhibition of Fbx4 by RNA interference stabilizes Pin2/TRF1 and promotes telomere shortening, thereby impairing cell growth. These results demonstrate that Fbx4 is a central regulator of Pin2/TRF1 protein abundance and that alterations in the stability of Pin2/TRF1 can have a dramatic impact on telomere length. Thus, Fbx4 may play a critical role in telomere maintenance.
Mesh Terms:
Adenosine Triphosphate, Cell Line, Cell Line, Tumor, DNA, Down-Regulation, F-Box Proteins, Genetic Vectors, Glutathione Transferase, Hela Cells, Humans, Immunoblotting, Immunoprecipitation, Mitosis, Protein Binding, Protein Isoforms, Protein Synthesis Inhibitors, RNA Interference, RNA, Messenger, Recombinant Proteins, Substrate Specificity, Telomere, Telomeric Repeat Binding Protein 1, Time Factors, Two-Hybrid System Techniques, Ubiquitin
Adenosine Triphosphate, Cell Line, Cell Line, Tumor, DNA, Down-Regulation, F-Box Proteins, Genetic Vectors, Glutathione Transferase, Hela Cells, Humans, Immunoblotting, Immunoprecipitation, Mitosis, Protein Binding, Protein Isoforms, Protein Synthesis Inhibitors, RNA Interference, RNA, Messenger, Recombinant Proteins, Substrate Specificity, Telomere, Telomeric Repeat Binding Protein 1, Time Factors, Two-Hybrid System Techniques, Ubiquitin
J. Biol. Chem.
Date: Jan. 13, 2006
PubMed ID: 16275645
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