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Breast cancer-specific gene 1 interacts with the mitotic checkpoint kinase BubR1

Oncogene volume 22, pages 7593–7599 (2003)Cite this article

Abstract

The abnormal expression of breast cancer-specific gene 1 (BCSG1) in malignant mammary epithelial cells is highly associated with the development and progression of breast cancer. A series of in vitro and in vivo studies performed in our laboratory and others have demonstrated that BCSG1 expression significantly stimulates proliferation, invasion, and metastasis of breast cancer cells. However, currently little is known about how BCSG1 exerts its oncogenic functions. To elucidate the cellular mechanisms underlying the effects of BCSG1 in breast cancer cells, we used a yeast two-hybrid system to screen for proteins that could associate with BCSG1. Through this screening, we identified the mitotic checkpoint protein BubR1 as a novel binding partner of BCSG1. The specific association of BCSG1 with BubR1 in breast cancer cells was demonstrated by immunoprecipitation and GST pull-down assays. Intriguingly, experiments conducted in four different cell lines all showed that exogenous expressions of BCSG1 consistently reduce the cellular levels of the BubR1 protein without affecting BubR1 mRNA expression. The tendency of endogenous BCSG1 expression coinciding with lower BubR1 protein levels was also observed in seven out of eight breast cancer cell lines. We further showed that the reducing effect of BCSG1 on BubR1 protein expression could be prevented by treating BCSG1-transfected cells with MG-132, a selective 26S proteasome inhibitor, implying that the proteasome machinery may be involved in the BCSG1-induced reduction of the BubR1 protein. Accompanied with a reduction of BubR1 protein level, BCSG1 expression resulted in multinucleation of breast cancer cells upon treatment with spindle inhibitor nocodazole, indicating an impaired mitotic checkpoint. Taken together, our novel findings suggest that BCSG1 may accelerate the progression of breast cancer at least in part by compromising the mitotic checkpoint control through inactivation of BubR1.

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Abbreviations

aa:

amino acid

APC:

anaphase-promoting complex

BCSG1:

breast cancer-specific gene 1

FBS:

fetal bovine serum

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

GST:

glutathione-S-transferase

IP:

immunoprecipitation

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Acknowledgements

We thank Dr Tim J Yen for the assistance in Western blotting to detect BubR1 in the BCSG1 immunocomplex and Dr Y Eric Shi for providing the BCSG1 expression vector (pCI-BCSG1) and the established clones of MDAMB435-BCSG1 and MDAMB435-neo. This study was supported by the Department of Veterans Affairs (Office of Research and Development, Medical Research Service) by Grant (1RO1CA83648-01) from National Cancer Institute, and by Grant (BC990960) from the US Army Medical Research and Development Command.

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Authors and Affiliations

  1. Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, 94304, CA, USA

    Anu Gupta, Satoru Inaba & Jingwen Liu

  2. Department of Biological Sciences, Stanford University, Stanford, 94305, CA, USA

    Oi Kwan Wong & Guowei Fang

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  1. Anu Gupta
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Correspondence to Jingwen Liu.

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Gupta, A., Inaba, S., Wong, O. et al. Breast cancer-specific gene 1 interacts with the mitotic checkpoint kinase BubR1. Oncogene 22, 7593–7599 (2003). https://doi.org/10.1038/sj.onc.1206880

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