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J. Cell Biol.,
Volume 140, Number 4, February 23, 1998 935-946
Unité de Génétique de la Différenciation, URA 1149, Centre National de la Recherche Scientifique, Département de Biologie
Moléculaire, Institut Pasteur, 75724 Paris, France
Abstract. We have recently shown that stable expression of an epitope-tagged cDNA of the hepatocyte-
enriched transcription factor, hepatocyte nuclear factor
(HNF)4, in dedifferentiated rat hepatoma H5 cells is
sufficient to provoke reexpression of a set of hepatocyte marker genes. Here, we demonstrate that the effects of HNF4 expression extend to the reestablishment
of differentiated epithelial cell morphology and simple
epithelial polarity. The acquisition of epithelial morphology occurs in two steps. First, expression of HNF4
results in reexpression of cytokeratin proteins and partial reestablishment of E-cadherin production. Only the transfectants are competent to respond to the synthetic
glucocorticoid dexamethasone, which induces the second step of morphogenesis, including formation of the
junctional complex and expression of a polarized cell
phenotype. Cell fusion experiments revealed that the
transfectant cells, which show only partial restoration
of E-cadherin expression, produce an extinguisher that
is capable of acting in trans to downregulate the E-cadherin gene of well-differentiated hepatoma cells. Bypass of this repression by stable expression of E-cadherin in H5 cells is sufficient to establish some
epithelial cell characteristics, implying that the morphogenic potential of HNF4 in hepatic cells acts via activation of the E-cadherin gene. Thus, HNF4 seems to integrate the genetic programs of liver-specific gene
expression and epithelial morphogenesis.
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