The DNA binding activity of the liver transaction factors LFB1 (HNF1) AND HNF4 varies coordinately in rat hepatocellular carcinoma

Stumpf, H; Senkel, Sabine; Rabes, Hartmut M.; Ryffel, Gerhart U.

doi:10.1093/carcin/16.1.143

Cited by 15 publications

(5 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whereas chemically induced HCC in rat failed to show a decrease in HNF4a (Stumpf et al, 1995), HNF4a expression showed a close correlation with HCC differentiation and was proposed to be a useful marker to assess the degree of HCC differentiation in humans (Ishiyama et al, 2003). A systematic investigation of human HCCs including microarray analysis has shown in some (Choi et al, 2004) but not all HCCs (Xu et al, 2001) a decrease in HNF4a.…”

Section: Hnf4a Reduces Proliferation Of Kidney Cells B Lucas Et Almentioning

confidence: 99%

“…Whereas no consistent changes in HNF4a were seen in chemically induced rat hepatomas (Stumpf et al, 1995), the analysis of human renal cell carcinoma (RCC) revealed that the abundance and the DNAbinding activity of HNF4a protein is frequently reduced in the carcinoma compared to the normal tissue (Sel et al, 1996). This finding was confirmed by comparing gene expression profiles of RCC with normal tissue showing 4.7-fold downregulation of HNF4a mRNA (Lenburg et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

HNF4α reduces proliferation of kidney cells and affects genes deregulated in renal cell carcinoma

et al. 2005

View full text Add to dashboard Cite

Section: Hnf4a Reduces Proliferation Of Kidney Cells B Lucas Et Almentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HNF4α reduces proliferation of kidney cells and affects genes deregulated in renal cell carcinoma

et al. 2005

View full text Add to dashboard Cite

“…In particular, the nuclear receptor HNF4 is a key regulator of both hepatocyte differentiation during embryonic development and maintenance of a differentiated phenotype in the adult 9–11. Differences in the biologic properties of experimental systems and tumor samples analyzed have led to conflicting reports concerning the role of HNFs in hepatocarcinogenesis 12–15. We therefore sought to elucidate the role of liver transcription factors in HCC progression by generating a new experimental model in which a minimally invasive slow‐growing transplantable differentiated mouse HCC (sgHCC) rapidly gives rise in vivo to a highly invasive dedifferentiated fast‐growing variant (fgHCC).…”

mentioning

confidence: 99%

Progression of HCC in mice is associated with a downregulation in the expression of hepatocyte nuclear factors

et al. 2004

View full text Add to dashboard Cite

Hepatocyte nuclear factors (HNF) play a critical role in development of the liver. Their roles during liver tumorigenesis and progression of hepatocellular carcinomas (HCC) are, however, poorly understood. To address the role of HNFs in tumor progression, we generated a new experimental model in which a highly differentiated slow-growing transplantable mouse HCC (sgHCC) rapidly gives rise in vivo to a highly invasive fast-growing dedifferentiated variant (fgHCC). This in vivo model has allowed us to investigate the fundamental mechanisms underlying HCC progression. A complete loss of cell polarity, a decrease in cell-cell and cell-extracellular matrix (ECM) adhesion, elevation of telomerase activity, and extinction of liver-specific gene expression accompanies tumor progression. Moreover, cells isolated from fgHCCs acquired the ability to proliferate rapidly in culture. These alterations were coupled with a reduced expression of several liver transcription factors including HNF4, a factor essential for hepatocyte differentiation. Forced re-expression of HNF4␣1 in cultured fgHCC cells reversed the progressive phenotype and induced fgHCC cells to reestablish an epithelium and reform cell-ECM contacts. Moreover, fgHCC cells that expressed HNF4␣1 also re-established expression of the profile of liver transcription factors and hepatic genes that are associated with a differentiated hepatocyte phenotype. Importantly, re-expression of HNF4␣1 in fgHCC reduced the proliferation rate in vitro and diminished tumor formation in congenic recipient mice. In conclusion, loss of HNF4 expression is an important determinant of HCC progression. Forced expression of this factor can promote reversion of tumors toward a less invasive highly differentiated slow-growing phenotype. (HEPATOLOGY 2004;39:1038 -1047 H epatocellular carcinoma (HCC) is one of the world's most common cancers, with chronic hepatitis B and C infection and prolonged exposure to hepatocarcinogens being the major risk factors. 1 The development of a malignant phenotype is considered a multi-step process that results from the accumulation of genetic alterations. The consequence of these alterations is the evolution of a tumor towards a more aggressive phenotype. HCC progression from a well differentiated to a less differentiated form is accompanied by striking changes in the morphological and genetic properties of the cells and is one of the most critical steps of liver tumorigenesis. 2,3 Hepatic tumor progression is defined by a decrease in differentiation, an extinction of tissue-specific gene expression, acceleration of cell proliferation, loss of epithelial morphology, increased invasiveness, and ultimately metastasis. While a variety of inter-and intracellular signaling pathways essential for the control of liver function and proliferation have been described, the mo-

show abstract

“…The protein-free inhibitor preparation was used at 1, 0.3, or 0.1 l in lanes 3 to 5 and 8 to 10, respectively. The arrowhead marks the HNF4␣-DNA complex, and the open terminal tag of HNF4␣, but also occurs using a monoclonal antibody raised against the ABCD domains of HNF4␣ (36).…”

Section: Discussionmentioning

confidence: 99%

Inhibitor of the Tissue-Specific Transcription Factor HNF4, a Potential Regulator in Early Xenopus Development

Peiler

Böckmann

Nakhei

et al. 2000

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

Hepatocyte nuclear factor 4␣ (HNF4␣) is an orphan receptor of the nuclear receptor superfamily and expressed in vertebrates as a tissue-specific transcription factor in liver, kidney, intestine, stomach, and pancreas. It also plays a crucial role in early embryonic development and has been identified as a maternal component in the Xenopus egg. We now report on an activity present in Xenopus embryos that inhibits the DNA binding of HNF4. This HNF4 inhibitor copurifies with a 25-kDa protein under nondenaturing conditions but can be separated from this protein by sodium dodecyl sulfate treatment. Protease treatment of the inhibitor results in a core fragment of about 5 kDa that retains full inhibitory activity. The activity of the HNF4 inhibitor can also be monitored in the absence of DNA, as it alters the mobility of the HNF4 protein in native polyacrylamide gels and the accessibility of antibodies. Comparing the activity of the HNF4 inhibitor with acyl coenzyme A's, recently proposed to be ligands of HNF4, we observe a more stringent specificity for the HNF4 inhibitor activity. Using deletion constructs of the HNF4 protein, we could show that the potential ligandbinding domain of HNF4 is not required, and thus the HNF4 inhibitor does not represent a classical ligand as defined for the nuclear receptor superfamily. Based on our previous finding that maternal HNF4 is abundantly present in Xenopus embryos but the target gene HNF1␣ is only marginally expressed, we propose that the HNF4 inhibitor functions in the embryo to restrict the activity of the maternal HNF4 proteins.Hepatocyte nuclear factor 4 (HNF4) constitutes transcription factor subfamily 2A (28), whose first member, HNF4␣ (NR2A1), has been identified as a factor interacting with promoter elements mediating liver-specific transcription (35). Based on the zinc finger motif of the DNA-binding domain and on a potential ligand-binding domain, HNF4 is classified as a member of the nuclear orphan receptor superfamily (33). Recently, it has been reported that acyl coenzyme A's (acylCoAs) are potential ligands of HNF4␣: acyl-CoAs containing fatty acids with 16 C residues or shorter act as agonists by increasing the DNA-binding potential of HNF4␣, whereas acyl-CoAs with 18 C residues or longer have antagonistic properties and inhibit DNA binding of HNF4␣ (11). HNF4␣ turned out to be present as well in nonhepatic cells such as kidney, intestine, stomach, and pancreas (23,38,45). The importance of HNF4␣ in gene control in tissues distinct from the liver has been documented by the fact that an inherited human disease is based on the expression of a mutated HNF4␣ gene in the ␤ cells of the endocrine pancreas, leading to maturity-onset diabetes of the young (MODY1 [42]). Most interestingly, another MODY gene identified in humans represents the tissuespecific transcription factor HNF1␣ (43), known to be tightly regulated by HNF4 (17,39,44).In addition to its role as a tissue-specific transcription factor, HNF4␣ is also a maternal component in the egg of Drosophila melano...

show abstract

The DNA binding activity of the liver transaction factors LFB1 (HNF1) AND HNF4 varies coordinately in rat hepatocellular carcinoma

Cited by 15 publications

References 0 publications

HNF4α reduces proliferation of kidney cells and affects genes deregulated in renal cell carcinoma

HNF4α reduces proliferation of kidney cells and affects genes deregulated in renal cell carcinoma

Progression of HCC in mice is associated with a downregulation in the expression of hepatocyte nuclear factors

Inhibitor of the Tissue-Specific Transcription Factor HNF4, a Potential Regulator in Early Xenopus Development

Contact Info

Product

Resources

About