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J. Biol. Chem., Vol. 278, Issue 32, 30005-30014, August 8, 2003

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Lysosomal and Proteasomal Degradation Play Distinct Roles in the Life Cycle of Cx43 in Gap Junctional Intercellular Communication-deficient and -competent Breast Tumor Cells^*

Hong Qin , Qing Shao, Suleiman A. Igdoura , Moulay A. Alaoui-Jamali ¶ and Dale W. Laird ||

From the Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 5C1, Canada, the Departments of Biology and Pathology, McMaster University, Hamilton, Ontario L85 4L8, Canada, and the ^¶Department of Medicine, Pharmacology, and Therapeutics and Centre for Translational Research in Cancer, Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec H3T 1E2, Canada

The present study was designed to determine the specific roles played by lysosomes and proteasomes in the degradation of Cx43 in both gap junctional intercellular communication-deficient MDA-MB-231 and -competent BICR-M1R_k cells. In MDA-MB-231 cells, immunolocalization and brefeldin A protein transport blocking studies revealed that there was a propensity for newly synthesized Cx43 to be transported to lysosomes. On the other hand, light and electron microscopic analysis of BICR-M1R_k cells showed that Cx43 gap junctions were prevalent with a subpopulation of intracellular Cx43 localized to lysosomes. In both cell types, Western blots revealed a notable increase in total cellular Cx43 in response to lysosome inhibitors. Interestingly, lactacystin inhibition of proteosomal degradation in MDA-MB-231 cells resulted in a marked increase in phosphorylated Cx43 at the expense of non-phosphorylated Cx43, and this change corresponded with an increase in "oversized" gap junction plaques. In BICR-M1R_k cells, lactacystin treatment partially prevented the BFA-induced loss of gap junctions. Together, our data suggests that lysosomes play a key role in not only degrading internalized gap junction in BICR-M1R_k cells but also in degrading Cx43 delivered from early secretory compartments to lysosomes in MDA-MB-231 cells. Overall proteasomal degradation regulates the stability of phosphorylated Cx43 and appears to promote the internalization of Cx43 from the cell surface.

Received for publication, January 20, 2003 , and in revised form, May 14, 2003.

^* This work was supported by the Canadian Breast Cancer Research Initiative 012079 and the Canadian Institutes of Health Research Grant MOP 12241 (to D. W. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a Canadian Institutes of Health Research Studentship.

^|| To whom correspondence should be addressed: Centre for Gap Junction Research, Dept. of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A-5C1, Canada. Tel.: 519-661-2111 (ext: 86827); Fax: 519-850-2562; E-mail: dwlaird{at}uwo.ca.

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