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Oncogene (2005) 24, 64186431
& 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00www.nature.com/oncHNF4a reduces proliferation of kidney cells and affects genes deregulated
in renal cell carcinomaBelen Lucas1, Karen Grigo1, Silke Erdmann1,Jorn Lausen1,2, Ludger Klein-Hitpass1 and
Gerhart URyffel*,11Institut fur Zellbiologie (Tumorforschung), Universitatsklinikum Essen, D-45122 Essen, GermanyHepatocyte nuclear factor 4a (HNF4a) is a tissue-specic
transcription factor known to regulate a large number of
genes in hepatocytes and pancreatic b cells. Although
HNF4a is highly expressed in some sections of the kidney,
little is known about its role in this organ and about
HNF4a-regulated genes in the kidney cells. The abundance and activity of HNF4a are frequently reduced in
renal cell carcinoma (RCC) indicating some tumor
suppressing function of HNF4a in renal cells. To
determine the potential role of HNF4a in RCC, we used
Flp recombinase-mediated gene integration to generate
human embryonic kidney cells (HEK293) that conditionally express wild-type or mutated HNF4a. Expression of
wild-type HNF4a but not of the mutants led to reduction
of proliferation and alterations of cell morphology. These
effects were reversible and induced at physiological
concentrations of HNF4a. Using gene expression proling
by microarrays, we determined genes regulated by
HNF4a. Interestingly, many of the genes regulated by
HNF4a have been shown to be deregulated in RCC
microarray studies. These genes (ACY1, WT1,
SELENBP1, COBL, EFHD1, AGXT2L1, ALDH5A1,
THEM2, ABCB1, FLJ14146, CSPG2, TRIM9 and
HEY1) are good candidates for genes whose activity is
changed upon the decrease of HNF4a in RCC.
Oncogene (2005) 24, 64186431. doi:10.1038/sj.onc.1208794;
published online 13 June 2005Keywords: HNF4a; proliferation; microarray; renal cell
carcinomaIntroductionIn the adult organism, hepatocyte nuclear factor 4a
(HNF4a) is a cell-specic transcription factor and seems
to play a crucial role in selective gene expression in liver,
kidney, intestine, pancreas and stomach (Sladek and
Seidel, 2001). In addition, HNF4a is necessary for
normal embryonic development, since the inactivation
of the gene in mice leads to early embryonic death due to
dysfunction of the visceral endoderm (Chen et al., 1994).
Rescue of embryos lacking HNF4a showed that HNF4a
is a key regulator essential for hepatocyte differentiation
(Li et al., 2000). This observation has been extended by
liver-specic HNF4a deletion in the mouse embryo that
revealed HNF4a as an essential hepatic factor to control
lipid homeostasis (Hayhurst et al., 2001)...