Abstract
Nuclear foci containing the promyelocytic leukemia protein (PML bodies), which occur in most cells, play a role in tumor suppression. Here, we demonstrate that CHFR, a mitotic checkpoint protein frequently inactivated in human cancers, is a dynamic component of PML bodies. Intermolecular fluorescence resonance energy transfer analysis identified a distinct fraction of CHFR that interacts with PML in living cells. This interaction modulates the nuclear distribution and mobility of CHFR. A trans-dominant mutant of CHFR that inhibits checkpoint function also prevents colocalization and interaction with PML. Conversely, the distribution and mobility of CHFR are perturbed in PML(-/-) cells, accompanied by aberrations in mitotic entry and the response to spindle depolymerization. Thus, PML bodies control the distribution, dynamics and function of CHFR. Our findings implicate the interaction between these tumor suppressors in a checkpoint response to microtubule poisons, an important class of anticancer drugs.
| Original language | English |
|---|---|
| Pages (from-to) | 1114-21 |
| Number of pages | 8 |
| Journal | Nature Structural and Molecular Biology |
| Volume | 11 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 2004 |
Keywords
- Animals
- Cell Cycle
- Cell Cycle Proteins/metabolism
- Cell Line
- Cell Nucleus/metabolism
- Chromosome Aberrations
- Cloning, Molecular
- DNA, Complementary/metabolism
- Fluorescence Resonance Energy Transfer
- Green Fluorescent Proteins/metabolism
- Humans
- Immunoprecipitation
- Intranuclear Inclusion Bodies/metabolism
- Mice
- Microscopy, Fluorescence
- Mitosis
- Models, Genetic
- Mutation
- Neoplasm Proteins/chemistry
- Nuclear Proteins/chemistry
- Poly-ADP-Ribose Binding Proteins
- Promyelocytic Leukemia Protein
- Protein Binding
- Recombinant Fusion Proteins/metabolism
- Time Factors
- Transcription Factors/chemistry
- Transfection
- Transgenes
- Tumor Suppressor Proteins
- Ubiquitin-Protein Ligases
- Xenopus
- Xenopus laevis
