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ß4 Integrin Transfection of UM-UC-2 (Human Bladder Carcinoma) Cells: Stable Expression of a Spontaneous Cytoplasmic Truncation Mutant with Rapid Loss of Clones Expressing Intact ß4¹

Laboratories of Head and Neck Cancer Biology [S. Y. K., T. S. N., S. G., T. E. C.] and Molecular Biology [N. J. B., M. I. L.], Department of Otolaryngology/Head and Neck Surgery, The University of Michigan, Ann Arbor, Michigan 48109-0506, and Department of Urology, M. D. Anderson Cancer Center, Houston, Texas 77030 [M. L., H. B. G.]

The 6ß4 integrin is a component of the hemidesmosome, the anchoring structure in the basal membrane of epithelial cells. 6ß4 expression is frequently altered in neoplastic cells. It is sometimes lost and sometimes overexpressed, which suggests that disruption of normal function is involved in neoplastic transformation. To examine the effect of this integrin on the growth and behavior of malignant cells that have lost ß4, we transfected a full-length ß4 cDNA into the UM-UC-2 cell line that expresses 6 but not ß4. Although large numbers of clones were obtained when a control vector was used in the transfection, only 12 clones could be isolated that expressed ß4. Of these, only two ß4-positive clones, clones 8 and 11, persisted long enough for further study. Clone 8 cells initially expressed ß4, but within 2 weeks, all positive cells were lost from the culture. Clone 11 persisted inculture and retained strong surface expression of 6ß4. Biochemical analysis and Western blotting revealed that this clone contained a truncated form of ß4 that had lost the distal cytoplasmic domain. We conclude that expression of wild-type ß4 in UM-UC-2 inhibits cell growth, presumably by an integrin-mediated signaling pathway. Clone 11 escaped from normal signaling because the cytoplasmic domain, a region essential for basal polar localization, was lost. The 6ß4 integrin appears to have tumor suppressor activity in epithelial tumors.

¹ Supported by grants from the Office of the Vice President for Research of the University of Michigan, the NIH-NCI CA56973 and NCI CA56973, the General Clinical Research Center Grant MO1-RR00042, and from the Asan Medical Center and Asan Institute for Life Science.

² Equal contributions as first author.

³ Present address: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Poongnap-Dong. Songpa-Ku, Seoul 138-040 Korea.

⁴ To whom requests for reprints should be addressed, at Laboratory of Head/Neck Cancer Biology. The University of Michigan, 6020 KHRI Campus Zip 0506, 1301 East Ann Street, Ann Arbor, MI 48109-0506.

Received 10/10/96. Accepted 11/ 7/96.

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