Title

Ectopic expression of the homeobox gene Cux-1 rescues calcineurin inhibition in mouse embryonic kidney cultures

Document Type

Article

Publication Date

2007

Abstract

Cux-1 is a murine homeobox gene structurally related to Drosophila cut. Cux-1 is highly expressed in the nephrogenic zone of the developing kidney, where its expression coincides with cell proliferation. Cux-1 functions as a transcriptional repressor of the cyclin kinase inhibitors (CKI) p21 and p27. Cux-1 DNA binding activity is negatively regulated by phosphorylation, and dephosphorylation of Cux-1 results in increased DNA binding. Transgenic mice ectopically expressing Cux-1 develop renal hyperplasia associated with the down-regulation of the CKI p27. Calcineurin A (CnA) α (-/-) mice display renal hypoplasia associated with the ectopic expression of p27. CnA is a serine/threonine phosphatase activated by intracellular calcium. Inhibiting CnA with cyclosporin A (CsA) leads to nephron deficit in rat metanephric organ cultures and apoptosis in various renal cell lines. To determine whether the ectopic expression of p27 in CnA-α -/- kidneys results from the down-regulation of Cux-1, metanephrol from embryonic Cux-1 transgenic and wild-type mice were harvested and cultured with CsA for 5 days. CsA treatment significantly inhibited growth of wild-type metanephrol. In contrast, CsA-treated Cux-1 transgenic kidney cultures were not growth inhibited, but showed high levels of cell proliferation in the nephrogenic zone. Moreover, in CsA-treated Cux-1 transgenic kidney cultures, p27 was not expressed in the nephrogenic zone, but only up-regulated in maturing glomeruli and tubules. Taken together, our results demonstrate that ectopic expression of Cux-1 can rescue the effects of CsA inhibition of CnA and suggest that Cux-1 may be regulated by calcineurin A. © 2006 Wiley-Liss, Inc.

Publication Title

Developmental Dynamics

Volume

236

Issue

1

First Page

184

Last Page

191

Comments

This article was published in Developmental Dynamics, Volume 236, Issue 1, Pages 184-191.

The published version is available at http://dx.doi.org/10.1002/dvdy.21003.

Copyright © 2007 Wiley.

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