Ectopic expression of the homeobox gene Cux-1 rescues calcineurin inhibition in mouse embryonic kidney cultures
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) Î± (-/-) 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-Î± -/- 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. Â© 2006 Wiley-Liss, Inc.
Alcalay, N. I.; Brantley, J. G.; Sharma, M.; Gooch, Jennifer L.; and Vanden Heuvel, G. B., "Ectopic expression of the homeobox gene Cux-1 rescues calcineurin inhibition in mouse embryonic kidney cultures" (2007). PCOM Scholarly Papers. 475.