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Cell cycle-dependent subcellular localization of the TSG101 protein and mitotic and nuclear abnormalities associated
1Program in Cancer Biology, Stanford University School of Medicine, Stanford, CA 94305-5120, USA.
Abstract:
TSG101 is a recently discovered tumor susceptibility gene whose functional inactivation in mouse fibroblasts results in cell transformation and the ability to form metastatic tumors in nude mice. Although restoration of TSG101 activity reverses tumorigenesis, neoplasia is irreversible in some cells, suggesting that permanent genetic alteration can occur during TSG101 inactivation. Here we describe studies that support this notion. We find that localization of TSG101 is cell cycle-dependent, occurring in the nucleus and Golgi complex during interphase, and in mitotic spindles and centrosomes during mitosis; cells made neoplastic by a deficiency in TSG101 expression show a series of mitosis-related abnormalities, including multiple microtubule organizing centers, aberrant mitotic spindles, abnormal distribution of metaphase chromatin, aneuploidy, and nuclear anomalies. Our findings suggest that TSG101 deficiency may lead to genome instability in addition to previously reported reversible neoplastic transformation.
Insights
Tumor susceptibility gene TSG101 inactivation causes cell transformation and metastasis. Its deficiency leads to mitosis abnormalities and potential genome instability, suggesting permanent genetic alterations.
Area of Science:
- Oncology
- Cell Biology
- Genetics
Background:
- TSG101 is a tumor susceptibility gene.
- Inactivating TSG101 in mouse fibroblasts causes cell transformation and metastasis.
- Neoplastic transformation can be irreversible, suggesting permanent genetic changes.
Purpose of the Study:
- To investigate the role of TSG101 in cell cycle regulation and mitosis.
- To determine if TSG101 deficiency leads to permanent genetic alterations.
Main Methods:
- Studied TSG101 localization during the cell cycle.
- Analyzed mitotic abnormalities in TSG101-deficient neoplastic cells.
- Observed multiple microtubule organizing centers, aberrant mitotic spindles, and aneuploidy.
Main Results:
- TSG101 localizes to the nucleus, Golgi, mitotic spindles, and centrosomes in a cell cycle-dependent manner.
- TSG101-deficient cells exhibit significant mitosis-related abnormalities.
- Observed aneuploidy and nuclear anomalies in neoplastic cells.
Conclusions:
- TSG101 deficiency disrupts normal mitosis.
- TSG101 inactivation may lead to genome instability.
- This instability contributes to irreversible neoplastic transformation.