Involvement of the telomeric protein Pin2/TRF1 in the regulation of the mitotic spindle.
Pin2/TRF1 was independently identified as a telomeric DNA-binding protein (TRF1) that regulates telomere length, and as a protein (Pin2) that can bind the mitotic kinase NIMA and suppress its lethal phenotype. We have previously demonstrated that Pin2/TRF1 levels are cell cycle-regulated and its overexpression induces mitotic arrest and then apoptosis. ... This Pin2/TRF1 activity can be potentiated by microtubule-disrupting agents, but suppressed by phosphorylation of Pin2/TRF1 by ATM; this negative regulation is critical in mediating for many, but not all, ATM-dependent phenotypes. Interestingly, Pin2/TRF1 specifically localizes to mitotic spindles in mitotic cells and affects the microtubule polymerization in vitro. These results suggest a role of Pin2/TRF1 in mitosis. However, nothing is known about whether Pin2/TRF1 affects the spindle function in mitotic progression. Here we characterized a new Pin2/TRF1-interacting protein, EB1, that was originally identified in our yeast two-hybrid screen. Pin2/TRF1 bound EB1 both in vitro and in vivo and they also co-localize at the mitotic spindle in cells. Furthermore, EB1 inhibits the ability of Pin2/TRF1 to promote microtubule polymerization in vitro. Given that EB1 is a microtubule plus end-binding protein, these results further confirm a specific interaction between Pin2/TRF1 and the mitotic spindle. More importantly, we have shown that inhibition of Pin2/TRF1 in ataxia-telangiectasia cells is able to fully restore their mitotic spindle defect in response to microtubule disruption, demonstrating for the first time a functional involvement of Pin2/TRF1 in mitotic spindle regulation.
Mesh Terms:
Antineoplastic Agents, Ataxia Telangiectasia, Cell Cycle Proteins, Cell Line, DNA-Binding Proteins, Glutathione Transferase, Hela Cells, Humans, Luminescent Proteins, Microtubule-Associated Proteins, Microtubules, Mitosis, Mitotic Spindle Apparatus, Protein Binding, Protein-Serine-Threonine Kinases, Recombinant Fusion Proteins, Telomere, Telomeric Repeat Binding Protein 1, Transfection, Tumor Suppressor Proteins
Antineoplastic Agents, Ataxia Telangiectasia, Cell Cycle Proteins, Cell Line, DNA-Binding Proteins, Glutathione Transferase, Hela Cells, Humans, Luminescent Proteins, Microtubule-Associated Proteins, Microtubules, Mitosis, Mitotic Spindle Apparatus, Protein Binding, Protein-Serine-Threonine Kinases, Recombinant Fusion Proteins, Telomere, Telomeric Repeat Binding Protein 1, Transfection, Tumor Suppressor Proteins
FEBS Lett.
Date: Mar. 13, 2002
PubMed ID: 11943150
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