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J. Biol. Chem., Vol. 277, Issue 18, 15592-15599, May 3, 2002

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A Novel Function of BCL-2 Overexpression in Regulatory Volume Decrease
ENHANCING SWELLING-ACTIVATED Ca²⁺ ENTRY AND Cl CHANNEL ACTIVITY^*

Meng-Ru Shen^§¶, Tzi-Peng Yang, and Ming-Jer Tang^**

From the  Department of Obstetrics and Gynecology and the  Department of Physiology, National Cheng Kung University Medical College, Tainan 701, Taiwan, Republic of China and ^§ University Laboratory of Physiology, Parks Road, University of Oxford, Oxford OX1 3PT, United Kingdom

The cellular function of the oncogene bcl-2, a key regulator of apoptosis, is still debated. The goal of this study was to explore the relationship between BCL-2 overexpression and cell volume regulation by using two independent models, Madin-Darby canine kidney (MDCK) cells stably transfected with BCL-2 and MDCK clones with inducible BCL-2 expression by the lac operator/repressor. BCL-2 overexpression enhanced the capability of regulatory volume decrease (RVD), a cellular defensive process against hypotonic stress. In various clones of MDCK cells, hypotonic stress induced an outwardly rectified Cl current that was significantly up-regulated by BCL-2 overexpression. Other fundamental characteristics of this channel were similar among different MDCK clones, such as sensitivity to Cl channel inhibitor, anion permeability, and time-dependent inactivation at more positive potential. Most importantly, BCL-2 overexpression up-regulates the swelling-activated Ca²⁺ transient that is a critical signaling for normal RVD and the activation of swelling-activated Cl channel in MDCK cells. BCL-2 overexpression also enhances the capacitative Ca²⁺ entry that can be differentiated from the swelling-activated Ca²⁺ transient by kinetic analysis and sensitivity to Gd³⁺. Moreover, neutralization of endogenous BCL-2 by antibody blocks the normal RVD response and the activation of swelling-activated Cl channel in human cervical cancer HT-3 cells. These results provide a new insight into the novel function of BCL-2 overexpression in the regulation of cell volume and ion flux.

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