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Cab45S promotes cell proliferation through SERCA2b inhibition and Ca2+ signaling

Oncogene volume 35, pages 35–46 (2016)Cite this article

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Abstract

Cytosolic Ca2+, closely related to endoplasmic reticulum (ER) Ca2+, plays a critical role in regulating cell proliferation and tumorigenesis. However, the role of ER lumen proteins in regulating cytosolic Ca2+ level remains poorly understood. Here, we find that the Cab45S, localizes in the ER lumen, inhibits sarco/ER Ca2+-ATPase 2b (SERCA2b) activity through its first EF-hand domain directly binding to the intra-lumenal loop 4 of SERCA2b, and reduces ER Ca2+. STIM1 activation, induced by the Cab45S-dependent drop in ER Ca2+, together with the upregulation of the plasma membrane Ca2+ channel TRPC1 ultimately increases extracellular Ca2+ influx. Furthermore, increased cytosolic Ca2+ level elicits Ca2+-NFAT signaling and promotes cell proliferation. Consistently, in cervical carcinoma patients, Cab45S is upregulated. Thus, our data reveal that the ability of Cab45S to inhibit SERCA2b activity is crucial for its role as a modulator of cell proliferation and tumor growth.

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Acknowledgements

We thank Weizhong Zhu (Nantong University) for providing with the Adenovirus containing GFP-tagged NFATc3; Zhili Li (Peking University Medical College), Xiaogai Yang (Peking University Medical College) and Weiguo Zhu (Peking University Medical College) for providing us with Panc1, SW1990, PC3 and SW480 cell lines, respectively. We also extend our thanks to Zhen Cai and Chuanmao Zhang (Peking University) for assistance with instruments and antibodies. This work was supported by the National Natural Science Foundation of China (31471280, 31271424).

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  1. L Chen and S Xu: These authors contributed equally to this work

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  1. Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, State Key Laboratory of Bio-membrane and Membrane Bio-engineering, College of Life Sciences, Peking University, Beijing, China

    L Chen, S Xu, Y Xu, W Lu, L Liu, D Yue, J Teng & J Chen

  2. Center for Quantitative Biology, Peking University, Beijing, China

    J Chen

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Chen, L., Xu, S., Xu, Y. et al. Cab45S promotes cell proliferation through SERCA2b inhibition and Ca2+ signaling. Oncogene 35, 35–46 (2016). https://doi.org/10.1038/onc.2015.56

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