We are interested in a new area of cancer biology, tumor suppression by the recently discovered CLCA family of calcium-activated chloride channel regulators. We have isolated several members of this gene family from mouse and human and characterized their expression in normal and cancer cells. We find that the genes are strongly induced by multiple physiological stresses, including cell detachment and DNA damage by chemotherapeutic agents. On the other hand, in rapidly growing tumor cell lines certain CLCA genes are downregulated by 20-200 fold, their expression diminishing with tumor progression. Re-establishment of CLCA gene expression inhibits tumor cell growth and survival and enhances sensitivity to cell detachment. These results demonstrate that CLCA proteins are part of a stress response pathway that must be inactivated during tumorigenesis. In the past few years, we have established the generality of these phenomena among several members of this gene family. In the next several years, we will focus on the human CLCA2 gene and its role as a tumor suppressor in breast cancer. We will establish why this gene is downregulated in cancer and whether it has therapeutic utility. In the longer term, and beyond the role of CLCAs in tumorigenesis,we are probing the structure and function of this mysterious family of proteins using the tools of molecular biology, genetics, genomics/proteomics, electrophysiology, and cell biology.


Publications (Last Ten Years):

Elble, R. C., Walia, V., Cheng, H., Connon, C., Mundhenk, L., Gruber, A., and Pauli, B. U. 2006. The putative chloride channel hCLCA2 has a single carboxy terminal transmembrane segment. Journal of Biological Chemistry, in press. (Corresponding author)

Mundhenk, L., Alfalah, M., Elble, R. C., Pauli, B. U., Naim, H. Y., Gruber, A. D. 2006. Both cleavage products of the mCLCA3 protein are secreted soluble proteins. Journal of Biological Chemistry, in press.

*Talhouk, R. S., *Elble, R. C., Bassam R., Daher M., Sfeir A, Hilda El-Khoury, Samar Hamoui and M. E. El-Sabban. 2005. A comprehensive profile of connexins in the murine mammary gland reveals a predominant role for Cx30 in lactogenesis. Cell and Tissue Research 319, 49-59. *equal contribution

Beckley, J. R., Pauli, B. U., and Elble, R. C. 2004. Detachment-inducible Cl- channel mCLCA5 inhibits proliferation of breast cancer cells. Journal of Biological Chemistry 279, 41634-41641. (Corresponding author)

Abdel-Ghany, M., Cheng, H-C, Elble, R.C., Lin, H, DiBiasio, J, and Pauli, B.U. 2003. The interacting binding domains of the beta 4 integrin and CLCA in Metastasis. Journal of Biological Chemistry 278, 49406-49416.

Elble, R. C., Ji, G., Nehrke, K., DiBiasio, J., Kingsley, P. D., Kotlikoff, M. I., and Pauli, B. U.. 2002. Molecular and functional characterization of a murine calcium-activated chloride channel expressed in smooth muscle. Journal of Biological Chemistry 277, 18586-18591. (Corresponding author)

Abdel-Ghany, M., Cheng, H-C., Elble, R. C., and Pauli, B. U. 2002. Focal adhesion kinase activated by beta 4 integrin ligation to mCLCA1 mediates early metastatic growth. Journal of Biological Chemistry 277, 34391-34400.

Gruber, A. D., Elble, R. C., and Pauli, B. U. 2002. Discovery and cloning of the CLCA gene family. In Calcium-activated chloride channels, volume 53 of Current Topics in Membranes. Ed. C. M. Fuller. Academic Press, London.

Elble, R. C., and Pauli, B. U. 2001. Tumor suppression by a pro-apoptotic calcium-activated chloride channel in mammary epithelium. Journal of Biological Chemistry 276, 40510-40517. (Corresponding author)

Abdel-Ghany, M., Cheng, H. C., Elble, R. C., and Pauli, B. U. 2001. Breast cancer metastasis of the lungs is mediated by beta 4 integrin adhesion to endothelial hCLCA2. Journal of Biological Chemistry 276, 25438-25446.

Gruber, A. D., Fuller, C. M., Elble, R. C., Benos, D., and Pauli, B. U. 2000. The CLCA gene family: A novel family of chloride channels. Current Genomics 1, 201-222.

Pauli, B.U., Abdel-Ghany, M., Cheng, H.C., Gruber, A.D., and Elble, R.C. 2000. Molecular characteristics and functional diversity of CLCA family members. Clinical and Experimental Pharmacology and Physiology 27, 901-905.

Fuller, C.M., H-L. Ji, A. Tousson, R. Elble, B.U. Pauli, and D.J. Benos. 2001. Ca2+-activated Cl- channels: a newly emerging anion transport family. Pfluegers Archiv-European Journal of Physiology, in press.

Cheng, H.C., Abdel-Ghany, M., Elble, R.C., and Pauli, B.U. 1998. Lung endothelial DPP IV promotes adhesion and metastasis of rat breast cancer cells via tumor cell surface-associated fibronectin. Journal of Biological Chemistry 273, 24207-24215.

Gruber, A.D., R.C. Elble, H. L. Ji, C. Fuller and B. U. Pauli. 1998. Genomic cloning, molecular and functional characterization of human intestinal chloride channel CLCA1. Genomics 54 (2), 200-214.

Gandhi, R., R. Elble, H. L. Ji, C. Fuller and B. U. Pauli. 1998. Molecular and functional characterization of a calcium-sensitive chloride channel from mouse lung. Journal of Biological Chemistry 273, 24207-24215.

Elble, R. C., J. Widom, A. D. Gruber, M. Abdel-Ghany, R. Levine, A. Goodwin, H. C. Cheng, and B. U. Pauli. 1997. Cloning and characterization of Lung-Endothelial Cell Adhesion Molecule-1 suggest it is an endothelial chloride channel. Journal of Biological Chemistry 272, 27853-27861.