Functional differences between wild-type and mutant-type BRCA1-associated protein 1 tumor suppressor against malignant mesothelioma cells.
Bottom Line: Transduction of the WT BAP1 vector into MM cells with homozygous deletion at the BAP1 3' side resulted in both inhibition of cell proliferation and anchorage-independent cell growth, whereas BAP1 mutants of a missense or C-terminal truncated form showed impaired growth inhibitory effects.Furthermore, using the MM cells with BAP1 deletion, we found that WT BAP1, and even a missense mutant, conferred a higher survival rate after IR compared to the control vector.Our results suggested that, whereas WT BAP1 suppresses MM cell proliferation and restores cell survival after IR damage, some mutant BAP1 may also moderately retain these functions.
Affiliation: Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan.Show MeSH
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Mentions: BAP1 contains two NLS at the COOH-terminus, and is primarily localized in the nucleus.17 We used immunofluorescence analysis to determine whether or not the BAP1 mutations have an effect on its subcellular localization, because four mutations were predicted to result in the loss of the both NLS and one in the NLS2 at the COOH-terminus among the seven mutations. As expected, NCI-H290 cells, which harbor WT BAP1, showed endogenous BAP1 expression primarily in the nucleus (Fig.2a). In contrast, Y-MESO-9 cells, which lack the NLS2, showed endogenous BAP1 mainly in the cytoplasm. These results suggested that nuclear localization of endogenous BAP1 is impaired primarily by the loss of NLS, which was consistent with a previous study.30
Affiliation: Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan.