A survivin-ran complex regulates spindle formation in tumor cells
Fang Xia1, Pedro M Canovas, Thomas M Guadagno
1Department of Cancer Biology, LRB428, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
Abstract:
Aberrant cell division is a hallmark of cancer, but the molecular circuitries of this process in tumor cells are not well understood. Here, we used a high-throughput proteomics screening to identify novel molecular partners of survivin, an essential regulator of mitosis overexpressed in cancer. We found that survivin associates with the small GTPase Ran in an evolutionarily conserved recognition in mammalian cells and Xenopus laevis extracts. This interaction is regulated during the cell cycle, involves Ran-GTP, requires a discrete binding interface centered on Glu65 in survivin, and is independent of the Ran effector Crm1. Disruption of a survivin-Ran complex does not affect the assembly of survivin within the chromosomal passenger complex or its cytosolic accumulation, but it inhibits the delivery of the Ran effector molecule TPX2 to microtubules. In turn, this results in aberrant mitotic spindle formation and chromosome missegregation in tumor, but not normal, cells. Therefore, survivin is a novel effector of Ran signaling, and this pathway may be preferentially exploited for spindle assembly in tumor cells.
Insights
Survivin, a key mitosis regulator, binds to the small GTPase Ran. This interaction is crucial for proper mitotic spindle formation, especially in cancer cells, revealing a novel cancer-specific pathway.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Aberrant cell division is a hallmark of cancer.
- The molecular mechanisms governing cell division in tumors are not fully understood.
- Survivin is an essential mitosis regulator overexpressed in various cancers.
Purpose of the Study:
- To identify novel molecular partners of survivin using high-throughput proteomics.
- To investigate the functional significance of survivin-interacting proteins in cancer cell division.
- To elucidate the role of survivin in Ran signaling pathways.
Main Methods:
- High-throughput proteomics screening to identify survivin-binding proteins.
- Biochemical assays to characterize the survivin-Ran interaction.
- Cellular experiments to assess the impact of disrupting the survivin-Ran complex on mitosis.
Main Results:
- Survivin was found to associate with the small GTPase Ran in a conserved manner.
- This interaction is cell-cycle regulated, dependent on Ran-GTP, and involves a specific binding site on survivin.
- Disruption of the survivin-Ran complex impaired TPX2 delivery to microtubules, leading to aberrant spindle formation and chromosome missegregation in tumor cells.
Conclusions:
- Survivin acts as a novel effector of Ran signaling.
- The survivin-Ran pathway is preferentially utilized for mitotic spindle assembly in tumor cells.
- Targeting this pathway could offer a strategy for cancer therapy.
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