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Stable Knockdown of Polycystin-1 Confers Integrin-21–Mediated Anoikis Resistance

Lorenzo Battini^*, Elena Fedorova^*, Salvador Macip, Xiaohong Li^*, Patricia D. Wilson^* and G. Luca Gusella^*

^* Division of Renal Medicine and Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York

Address correspondence to: Dr. G. Luca Gusella, Mount Sinai School of Medicine, One Gustave Levy Place, Box 1243, New York, NY 10029. Phone: 212-241-9597; Fax: 212-987-0389; E-mail: luca.gusella{at}mssm.edu

Received for publication March 16, 2006. Accepted for publication August 17, 2006.

The mechanisms of action of polycystin-1 (PC1) have been difficult to dissect because of its interaction with multiple factors, the heterogeneity of the genetic mutations, and the complexity of the experimental animal models. Here, stable knockdown of PC1 in MDCK epithelial cells was achieved by lentiviral-mediated delivery of a specific small interfering RNA for PKD1. The reduction of PC1 expression prevented tubulogenesis in three-dimensional collagen type I culture in response to hepatocyte growth factor and induced formation of cysts. PC1 knockdown created a condition of haploinsufficiency that led to hyperproliferation, increased adhesion to collagen type I, and increased apoptosis. It was shown that the suppression of PC1 was associated with the increased expression of integrin-21 and reduced apoptosis in cells grown on collagen type I. The engagement of integrin-21 seemed to be essential for the survival because PC1 knockdown cells were significantly less susceptible to anoikis by a mechanism that was reversible by anti–integrin-21 blocking antibodies. Overall, these data link integrin-21 to some of the biologic functions that are ascribed to PC1 and establish the potential of this approach for the direct study of PC1 functions in a genetically defined background. Furthermore, these findings indicate that reduction of PC1 expression levels, rather than the loss of heterozygosity, may be sufficient to induce cystogenesis.

This article has been cited by other articles:

				L. Battini, S. Macip, E. Fedorova, S. Dikman, S. Somlo, C. Montagna, and G. L. Gusella Loss of polycystin-1 causes centrosome amplification and genomic instability Hum. Mol. Genet., September 15, 2008; 17(18): 2819 - 2833. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673