Deregulated expression of the homeobox gene Cux-1 in transgenic mice results in downregulation of p27(kip1) expression during nephrogenesis, glomerular abnormalities, and multiorgan hyperplasia.
Cux-1 is a murine homeobox gene that is highly expressed in the developing kidney with expression restricted to the nephrogenic zone. Cux-1 is highly expressed in cyst epithelium of polycystic kidneys from C57BL/6J-cpk/cpk mice, but not in kidneys isolated from age-matched phenotypically normal littermates. To further elucidate the role of Cux-1 in renal development, we generated transgenic mice expressing Cux-1 under the control of the CMV immediate early gene promoter. Mice constitutively expressing Cux-1 developed multiorgan hyperplasia and organomegaly, but not an overall increase in body size. Transgenic kidneys were enlarged 50% by 6 weeks of age, with the increased growth primarily restricted to the cortex. Proliferating cells were found in proximal and distal tubule epithelium throughout the cortex, and the squamous epithelium that normally lines Bowman's capsule was replaced with proximal tubule epithelium. However, the total number of nephrons was not increased. In the developing kidneys of transgenic mice, Cux-1 was ectopically expressed in more highly differentiated tubules and glomeruli, and this was associated with reduced expression of the cyclin kinase inhibitor, p27. Transient transfection experiments revealed that Cux-1 is an inhibitor of p27 promoter activity. These results suggest that Cux-1 regulates cell proliferation during early nephrogenesis by inhibiting expression of p27.
Ledford
Aric W
AW
Department of Biology, East Carolina University, Greenville, NC 27858, USA.
Brantley
Jennifer G
JG
Kemeny
Gabor
G
Foreman
Tonia L
TL
Quaggin
Susan E
SE
Igarashi
Peter
P
Oberhaus
Stephanie M
SM
Rodova
Marianna
M
Calvet
James P
JP
Vanden Heuvel
Gregory B
GB
D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D002455:Cell Division; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017931:DNA Primers; D015536:Down-Regulation; D005314:Embryonic and Fetal Development; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D017781:Genes, Immediate-Early; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000196:embryology / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000002:abnormalities; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D025521:Tumor Suppressor Proteins / Q000235:genetics*
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D017931:DNA Primers; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27