Phenotypic effects of the forced expression of HNF4 and HNF1α are conditioned by properties of the recipient cell

Abstract

Tagged versions of HNF4 or HNF1alpha cDNAs in expression vectors have been introduced by transient and stable transfection into three cell lines of hepatic origin that all fail to express these two liver-enriched transcription factors and hepatic functions. C2 and H5 cells are dedifferentiated rat hepatoma variants and WIF12-E cells are human fibroblast-rat hepatoma hybrids with a reduced complement of human chromosomes. Transfectants were analyzed for the expression state of the endogenous genes coding for these transcription factors and for hepatic functions. Each cell line showed a different response to the forced expression of the transcription factors. In C2 cells, no measurable effect was observed, either upon transitory or stable expression. H5 cells reexpressed the endogenous HNF4 gene only upon transient HNF1alpha transfection, and the endogenous HNF1alpha gene only in stable HNF4 transfectants. WIF12-E cells responded to the forced transient or stable expression of either HNF1alpha or HNF4 by cross-activation of the corresponding endogenous gene. In addition, the stable transfectants reexpress HNF3alpha and C/EBPalpha, as well as all of the hepatic functions examined. Hybrid cells similar to WIF12-E had previously been observed to show pleiotropic reexpression of the hepatic phenotype in parallel with loss of human chromosome 2. For the stable WIF12-E transfectants, it was verified that reexpression of the hepatic phenotype was not due to loss of human chromosome 2. The demonstration of reciprocal cross-regulation between HNF4 and HNF1alpha in transient as well as stable transfectants implies that direct effects are involved.

FOXA1: Growth inhibitor and a favorable prognostic factor in human breast cancer

“…These findings thus further support a growth inhibitory role for FOXA1 in breast cancer. Cell‐type dependent transcriptional activity of FOXA proteins is not unique for breast cancer and has also been demonstrated in hepatoma and neuroblastoma cells 28, 29. Interestingly, another member of the FOX family, FOXO1 (also known as FKHR) also shows cell‐type dependent activity on the ER pathway: repression in HepG2 cells and activation in MCF‐7 cells 30, 31…”

“…Cell-type dependent transcriptional activity of FOXA proteins is not unique for breast cancer and has also been demonstrated in hepatoma and neuroblastoma cells. 28,29 Interestingly, another member of the FOX family, FOXO1 (also known as FKHR) also shows cell-type dependent activity on the ER pathway: repression in HepG2 cells and activation in MCF-7 cells. 30,31 Two global screens for ERa-responsive genes identified a role for FOXA1 in the activation of genes that contain both ERE and FOXA1 consensus sites in their promoter region.…”

Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α

“…The self‐stimulation of HNF4α on its own promoter, and the reciprocal regulatory loop between HNF4α and HNF1α has been reported for more than two decades . This positive feedback loop between HNF4α and HNF1α needs a break, such as self‐inhibition of HNF1α, to sustain constant intracellular levels of HNF4α and HNF1α in vivo.…”

“…The self-stimulation of HNF4α on its own promoter, and the reciprocal regulatory loop between HNF4α and HNF1α has been reported for more than two decades. [18][19][20] This positive feedback loop between HNF4α and HNF1α needs a break, such as self-inhibition of HNF1α, 21 to sustain constant intracellular levels of HNF4α and HNF1α in vivo. Surprisingly, a following study indicated that HNF4α was capable of not only self-activating its own promoter, but also inducing a highly synergistic selfactivation in HeLa cells via interacting with HNF1α and HNF6.…”