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Hepatomegaly in transgenic mice expressing the homeobox gene Cux‐1
Author(s) -
Vanden Heuvel Gregory B.,
Brantley Jennifer G.,
Alcalay Neal I.,
Sharma Madhulika,
Kemeny Gabor,
Warolin Joshua,
Ledford Aric W.,
Pinson David M.
Publication year - 2005
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20091
Subject(s) - biology , transgene , microbiology and biotechnology , cell growth , cyclin , genetically modified mouse , cyclin d1 , hepatocyte , cell cycle , cancer research , cell , gene , genetics , in vitro
Cux‐1 is a member of a family of homeobox genes structurally related to Drosophila Cut. Mammalian Cut proteins function as transcriptional repressors of genes specifying terminal differentiation in multiple cell lineages. In addition, mammalian Cut proteins serve as cell‐cycle‐dependent transcriptional factors in proliferating cells, where they function to repress expression of the cyclin kinase inhibitors p21 and p27. Previously we showed that transgenic mice expressing Cux‐1 under control of the CMV immediate early gene promoter develop multiorgan hyperplasia. Here we show that mice constitutively expressing Cux‐1 exhibit hepatomegaly correlating with an increase in cell proliferation. In addition, the increase in Cux‐1 expression in transgenic livers was associated with a decrease in p21, but not p27, expression. Within transgenic livers, Cux‐1 was ectopically expressed in a population of small cells, but not in mature hepatocytes, and many of these small cells expressed markers of proliferation. Transgenic livers showed an increase in α‐smooth muscle actin, indicating activation of hepatic stellate cells, and an increase in cells expressing chromogranin‐A, a marker for hepatocyte precursor cells. Morphological analysis of transgenic livers revealed inflammation, hepatocyte swelling, mixed cell foci, and biliary cell hyperplasia. These results suggest that increased expression of Cux‐1 may play a role in the activation of hepatic stem cells, possibly through the repression of the cyclin kinase inhibitor p21. © 2005 Wiley‐Liss, Inc.