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• W2012053529 abstract "Background & Aims: The hepatocyte nuclear factor 6 (HNF6 or ONECUT-1) protein is a cell-type specific transcription factor that regulates expression of hepatocyte-specific genes. Using hepatocytes for chromatin immunoprecipitation (ChIP) assays, the HNF6 protein was shown to associate with cell cycle regulatory promoters. Here, we examined whether increased levels of HNF6 stimulate hepatocyte proliferation during mouse liver regeneration. Methods: Tail vein injection of adenovirus expressing the HNF6 complementary DNA was used to increase hepatic HNF6 levels during mouse liver regeneration induced by partial hepatectomy, and DNA replication was determined by bromodeoxyuridine incorporation. Cotransfection and ChIP assays were used to determine transcriptional target promoters. Results: Elevated expression of HNF6 during mouse liver regeneration causes a significant increase in the number of hepatocytes entering DNA replication (S phase), and mouse hepatoma Hepa1-6 cells diminished for HNF6 levels by small interfering RNA transfection exhibit a 50% reduction in S phase following serum stimulation. This stimulation in hepatocyte S-phase progression was associated with increased expression of the hepatocyte mitogen tumor growth factor α and the cell cycle regulators cyclin D1 and Forkhead box m1 (Foxm1) transcription factor. Cotransfection and ChIP assays show that tumor growth factor α, cyclin D1, and HNF6 promoter regions are direct transcriptional targets of the HNF6 protein. Coimmunoprecipitation assays with regenerating mouse liver extracts reveal an association between HNF6 and FoxM1 proteins, and cotransfection assays show that HNF6 stimulates Foxm1 transcriptional activity. Conclusions: These mouse liver regeneration studies show that increased HNF6 levels stimulate hepatocyte proliferation through transcriptional induction of cell cycle regulatory genes. Background & Aims: The hepatocyte nuclear factor 6 (HNF6 or ONECUT-1) protein is a cell-type specific transcription factor that regulates expression of hepatocyte-specific genes. Using hepatocytes for chromatin immunoprecipitation (ChIP) assays, the HNF6 protein was shown to associate with cell cycle regulatory promoters. Here, we examined whether increased levels of HNF6 stimulate hepatocyte proliferation during mouse liver regeneration. Methods: Tail vein injection of adenovirus expressing the HNF6 complementary DNA was used to increase hepatic HNF6 levels during mouse liver regeneration induced by partial hepatectomy, and DNA replication was determined by bromodeoxyuridine incorporation. Cotransfection and ChIP assays were used to determine transcriptional target promoters. Results: Elevated expression of HNF6 during mouse liver regeneration causes a significant increase in the number of hepatocytes entering DNA replication (S phase), and mouse hepatoma Hepa1-6 cells diminished for HNF6 levels by small interfering RNA transfection exhibit a 50% reduction in S phase following serum stimulation. This stimulation in hepatocyte S-phase progression was associated with increased expression of the hepatocyte mitogen tumor growth factor α and the cell cycle regulators cyclin D1 and Forkhead box m1 (Foxm1) transcription factor. Cotransfection and ChIP assays show that tumor growth factor α, cyclin D1, and HNF6 promoter regions are direct transcriptional targets of the HNF6 protein. Coimmunoprecipitation assays with regenerating mouse liver extracts reveal an association between HNF6 and FoxM1 proteins, and cotransfection assays show that HNF6 stimulates Foxm1 transcriptional activity. Conclusions: These mouse liver regeneration studies show that increased HNF6 levels stimulate hepatocyte proliferation through transcriptional induction of cell cycle regulatory genes. Liver regeneration induced by two-thirds partial hepatectomy results in synchronous induction of hepatocyte proliferation through collaborative stimulation between the hepatocyte mitogens hepatocyte growth factor and tumor growth factor (TGF)-α and the cytokine interleukin-6.1Fausto N. Liver regeneration.J Hepatol. 2000; 32: 19-31Abstract Full Text PDF PubMed Google Scholar, 2Michalopoulos G.K. DeFrances M.C. Liver regeneration.Science. 1997; 276: 60-66Crossref PubMed Scopus (2853) Google Scholar, 3Taub R. Liver regeneration from myth to mechanism.Nat Rev Mol Cell Biol. 2004; 5: 836-847Crossref PubMed Scopus (1230) Google Scholar Activation of the Ras/mitogen-activated protein kinase signaling pathway drives cell cycle progression by temporal expression of cyclin regulatory subunits, which activate their corresponding cyclin-dependent kinases (CDKs) through complex formation.4Massague J. G1 cell-cycle control and cancer.Nature. 2004; 432: 298-306Crossref PubMed Scopus (941) Google Scholar Progression into DNA replication (S phase) requires phosphorylation of the retinoblastoma protein by either the Cdk4/Cdk6 proteins in complex with cyclin D or Cdk2 in complex with cyclin E.4Massague J. G1 cell-cycle control and cancer.Nature. 2004; 432: 298-306Crossref PubMed Scopus (941) Google Scholar Hyperphosphorylated retinoblastoma dissociates from the E2F transcription factor and alleviates inhibition of E2F to allow transcriptional stimulation of S-phase–promoting genes. Earlier expression of cyclin D1 is associated with stimulating hepatocyte DNA replication in both rodent liver regeneration models and primary hepatocyte cultures.5Albrecht J.H. Hansen L.K. Cyclin D1 promotes mitogen-independent cell cycle progression in hepatocytes.Cell Growth Differ. 1999; 10: 397-404PubMed Google Scholar, 6Ledda-Columbano G.M. Pibiri M. Loi R. Perra A. Shinozuka H. Columbano A. Early increase in cyclin-D1 expression and accelerated entry of mouse hepatocytes into S phase after administration of the mitogen 1, 4-bis[2-(3,5-dichloropyridyloxy)] benzene.Am J Pathol. 2000; 156: 91-97Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 7Pibiri M. Ledda-Columbano G.M. Cossu C. Simbula G. Menegazzi M. Shinozuka H. Columbano A. Cyclin D1 is an early target in hepatocyte proliferation induced by thyroid hormone (T3).FASEB J. 2001; 15: 1006-1013Crossref PubMed Scopus (117) Google Scholar Stimulation of the Cdk1/cyclin B complex and expression of Polo-like kinase 1 and Aurora kinases are required for mitotic progression by phosphorylating protein substrates essential for orchestrating mitosis.4Massague J. G1 cell-cycle control and cancer.Nature. 2004; 432: 298-306Crossref PubMed Scopus (941) Google Scholar, 8Barr F.A. Sillje H.H. Nigg E.A. Polo-like kinases and the orchestration of cell division.Nat Rev Mol Cell Biol. 2004; 5: 429-440Crossref PubMed Scopus (885) Google Scholar, 9Meraldi P. Honda R. Nigg E.A. Aurora kinases link chromosome segregation and cell division to cancer susceptibility.Curr Opin Genet Dev. 2004; 14: 29-36Crossref PubMed Scopus (281) Google Scholar In addition to assembly with a cyclin regulatory subunit, activation of CDK kinase activity requires CDK dephosphorylation by the Cdc25 protein phosphatase family in which Cdc25A activates Cdk2 during G1/S transition and both Cdc25B and Cdc25C activate Cdk1 for progression into mitosis.10Nilsson I. Hoffmann I. Cell cycle regulation by the Cdc25 phosphatase family.Prog Cell Cycle Res. 2000; 4: 107-114Crossref PubMed Scopus (378) Google Scholar The CIP/KIP family of CDK inhibitor proteins p21Cip1 and p27Kip1 also negatively regulates CDK activity through protein complex formation.4Massague J. G1 cell-cycle control and cancer.Nature. 2004; 432: 298-306Crossref PubMed Scopus (941) Google Scholar, 11Sherr C.J. Roberts J.M. CDK inhibitors positive and negative regulators of G1-phase progression.Genes Dev. 1999; 13: 1501-1512Crossref PubMed Scopus (5072) Google Scholar To facilitate S-phase progression, the CDK inhibitor proteins are phosphorylated by the Cdk2/cyclin E complex and are subsequently targeted for degradation by the ubiquitin-mediated proteasome pathway.12Nakayama K.I. Hatakeyama S. Nakayama K. Regulation of the cell cycle at the G1-S transition by proteolysis of cyclin E and p27Kip1.Biochem Biophys Res Commun. 2001; 282: 853-860Crossref PubMed Scopus (201) Google Scholar, 13Pagano M. Control of DNA synthesis and mitosis by the Skp2-p27-Cdk1/2 axis.Mol Cell. 2004; 14: 414-416Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar The mammalian Forkhead box (Fox) family of transcription factors consists of more than 50 proteins14Kaestner K.H. Knochel W. Martinez D.E. Unified nomenclature for the winged helix/forkhead transcription factors.Genes Dev. 2000; 14: 142-146PubMed Google Scholar that share homology in the winged helix DNA binding domain (DBD).15Clark K.L. Halay E.D. Lai E. Burley S.K. Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5.Nature. 1993; 364: 412-420Crossref PubMed Scopus (1077) Google Scholar, 16Marsden I. Jin C. Liao X. Structural changes in the region directly adjacent to the DNA-binding helix highlight a possible mechanism to explain the observed changes in the sequence-specific binding of winged helix proteins.J Mol Biol. 1998; 278: 293-299Crossref PubMed Scopus (62) Google Scholar Expression of Foxm1 is found in all proliferating mammalian cells and tumor-derived cell lines and is extinguished in terminally differentiated cells that exit the cell cycle.17Korver W. Roose J. Clevers H. The winged-helix transcription factor Trident is expressed in cycling cells.Nucleic Acids Res. 1997; 25: 1715-1719Crossref PubMed Scopus (205) Google Scholar, 18Luscher-Firzlaff J.M. Westendorf J.M. Zwicker J. Burkhardt H. Henriksson M. Muller R. Pirollet F. Luscher B. Interaction of the fork head domain transcription factor MPP2 with the human papilloma virus 16 E7 protein enhancement of transformation and transactivation.Oncogene. 1999; 18: 5620-5630Crossref PubMed Scopus (98) Google Scholar, 19Yao K.M. Sha M. Lu Z. Wong G.G. Molecular analysis of a novel winged helix protein, WIN. Expression pattern, DNA binding property, and alternative splicing within the DNA binding domain.J Biol Chem. 1997; 272: 19827-19836Crossref PubMed Scopus (114) Google Scholar, 20Ye H. Kelly T.F. Samadani U. Lim L. Rubio S. Overdier D.G. Roebuck K.A. Costa R.H. Hepatocyte nuclear factor 3/fork head homolog 11 is expressed in proliferating epithelial and mesenchymal cells of embryonic and adult tissues.Mol Cell Biol. 1997; 17: 1626-1641Crossref PubMed Scopus (308) Google Scholar Transcription of the mouse Foxm1 locus results in 3 differentially spliced messenger RNAs (mRNAs) that are almost identical in sequence but differ by the addition of 2 small exons; the Foxm1b isoform (HFH-11B or human FoxM1b) contains no additional exons, whereas the Foxm1c (Trident, WIN, or MPP2) and Foxm1a (HFH-11A) isoforms contain 1 or 2 additional exons, respectively.18Luscher-Firzlaff J.M. Westendorf J.M. Zwicker J. Burkhardt H. Henriksson M. Muller R. Pirollet F. Luscher B. Interaction of the fork head domain transcription factor MPP2 with the human papilloma virus 16 E7 protein enhancement of transformation and transactivation.Oncogene. 1999; 18: 5620-5630Crossref PubMed Scopus (98) Google Scholar, 19Yao K.M. Sha M. Lu Z. Wong G.G. Molecular analysis of a novel winged helix protein, WIN. Expression pattern, DNA binding property, and alternative splicing within the DNA binding domain.J Biol Chem. 1997; 272: 19827-19836Crossref PubMed Scopus (114) Google Scholar, 20Ye H. Kelly T.F. Samadani U. Lim L. Rubio S. Overdier D.G. Roebuck K.A. Costa R.H. Hepatocyte nuclear factor 3/fork head homolog 11 is expressed in proliferating epithelial and mesenchymal cells of embryonic and adult tissues.Mol Cell Biol. 1997; 17: 1626-1641Crossref PubMed Scopus (308) Google Scholar, 21Korver W. Roose J. Heinen K. Weghuis D.O. de Bruijn D. van Kessel A.G. Clevers H. The human TRIDENT/HFH-11/FKHL16 gene structure, localization, and promoter characterization.Genomics. 1997; 46: 435-442Crossref PubMed Scopus (85) Google Scholar During mouse liver regeneration, expression of the Foxm1 transcription factor is induced in mid-G1 phase of the cell cycle and its expression continues during S phase and mitosis.20Ye H. Kelly T.F. Samadani U. Lim L. Rubio S. Overdier D.G. Roebuck K.A. Costa R.H. Hepatocyte nuclear factor 3/fork head homolog 11 is expressed in proliferating epithelial and mesenchymal cells of embryonic and adult tissues.Mol Cell Biol. 1997; 17: 1626-1641Crossref PubMed Scopus (308) Google Scholar, 22Ye H. Holterman A. Yoo K.W. Franks R.R. Costa R.H. Premature expression of the winged helix transcription factor HFH-11B in regenerating mouse liver accelerates hepatocyte entry into S-phase.Mol Cell Biol. 1999; 19: 8570-8580Crossref PubMed Scopus (165) Google Scholar Liver regeneration studies with mice in which the albumin promoter-enhancer Cre recombinase mediated conditional deletion of the Foxm1 LoxP/LoxP (fl/fl) targeted allele in adult hepatocytes showed that Foxm1 is required for high levels of regenerating hepatocyte DNA replication and is essential for mitosis.23Wang X. Kiyokawa H. Dennewitz M.B. Costa R.H. The Forkhead Box m1b transcription factor is essential for hepatocyte DNA replication and mitosis during mouse liver regeneration.Proc Natl Acad Sci U S A. 2002; 99: 16881-16886Crossref PubMed Scopus (271) Google Scholar The FoxM1 protein was shown to be essential for diminishing nuclear accumulation of CDK inhibitor proteins p21Cip1 and p27Kip1 and for transcription of Cdc25B phosphatase required for activating Cdk1.23Wang X. Kiyokawa H. Dennewitz M.B. Costa R.H. The Forkhead Box m1b transcription factor is essential for hepatocyte DNA replication and mitosis during mouse liver regeneration.Proc Natl Acad Sci U S A. 2002; 99: 16881-16886Crossref PubMed Scopus (271) Google Scholar, 24Kalinichenko V.V. Major M. Wang X. Petrovic V. Kuechle J. Yoder H.M. Shin B. Datta A. Raychaudhuri P. Costa R.H. Forkhead Box m1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor.Genes Dev. 2004; 18: 830-850Crossref PubMed Scopus (322) Google Scholar Moreover, albumin promoter-enhancer Cre recombinase Foxm1−/− hepatocytes fail to proliferate and are highly resistant to formation of hepatocellular carcinoma in response to a diethylnitrosamine/phenobarbital liver tumor induction protocol.24Kalinichenko V.V. Major M. Wang X. Petrovic V. Kuechle J. Yoder H.M. Shin B. Datta A. Raychaudhuri P. Costa R.H. Forkhead Box m1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor.Genes Dev. 2004; 18: 830-850Crossref PubMed Scopus (322) Google Scholar Foxm1−/− mouse embryos die in utero between 13.5 and 17.5 days of gestation due to severe defects in liver development and a failure to form intrahepatic bile ducts.25Krupczak-Hollis K. Wang X. Kalinichenko V.V. Gusarova G.A. Wang I.-C. Dennewitz M.B. Yoder H.M. Kiyokawa H. Kaestner K.H. Costa R.H. The mouse Forkhead Box m1 transcription factor is essential for hepatoblast mitosis and development of intrahepatic bile ducts and vessels during liver morphogenesis.Dev Biol. 2004; 276: 74-88Crossref PubMed Scopus (169) Google Scholar These phenotypes were associated with a 75% reduction in the number of hepatoblasts due to defective mitotic progression. The hepatocyte nuclear factor 6 (HNF6) or ONECUT-1 transcription factor binds to DNA as a monomer utilizing a C-terminal DBD consisting of a single cut and homeodomain, which is also known as the “ONECUT” DBD.26Jacquemin P. Lannoy V.J. Rousseau G.G. Lemaigre F.P. OC-2, a novel mammalian member of the ONECUT class of homeodomain transcription factors whose function in liver partially overlaps with that of hepatocyte nuclear factor-6.J Biol Chem. 1999; 274: 2665-2671Crossref PubMed Scopus (86) Google Scholar, 27Lemaigre F.P. Durviaux S.M. Truong O. Lannoy V.J. Hsuan J.J. Rousseau G.G. Hepatocyte nuclear factor 6, a transcription factor that contains a novel type of homeodomain and a single cut domain.Proc Natl Acad Sci U S A. 1996; 93: 9460-9464Crossref PubMed Scopus (128) Google Scholar, 28Rausa F. Samadani U. Ye H. Lim L. Fletcher C.F. Jenkins N.A. Copeland N.G. Costa R.H. The cut-homeodomain transcriptional activator HNF-6 is coexpressed with its target gene HNF-3β in the developing murine liver and pancreas.Dev Biol. 1997; 192: 228-246Crossref PubMed Scopus (156) Google Scholar, 29Samadani U. Costa R.H. The transcriptional activator hepatocyte nuclear factor six regulates liver gene expression.Mol Cell Biol. 1996; 16: 6273-6284Crossref PubMed Scopus (131) Google Scholar Recent NMR studies of the HNF6 DBD showed that the HNF6 cut domain folds into a topology homologous to the Oct-1 POU DBD, even though there is no sequence homology between the cut and POU domain sequences.30Sheng W. Yan H. Rausa F.M.I. Costa R.H. Liao X. Structure of the hepatocyte nuclear factor 6α (HNF-6α) and its interaction with DNA.J Biol Chem. 2004; 279: 33928-33936Crossref PubMed Scopus (13) Google Scholar Interestingly, the POU homeodomain GHF1/Pit1, Brn1, Oct-2, and Oct-3 transcription factors play essential roles in stimulating cellular proliferation and regulating expression of cell-type specific genes.31Castrillo J.L. Theill L.E. Karin M. Function of the homeodomain protein GHF1 in pituitary cell proliferation.Science. 1991; 253: 197-199Crossref PubMed Scopus (215) Google Scholar, 32Goodall J. Martinozzi S. Dexter T.J. Champeval D. Carreira S. Larue L. Goding C.R. Brn-2 expression controls melanoma proliferation and is directly regulated by beta-catenin.Mol Cell Biol. 2004; 24: 2915-2922Crossref PubMed Scopus (102) Google Scholar, 33Wang P. Branch D.R. Bali M. Schultz G.A. Goss P.E. Jin T. The POU homeodomain protein OCT3 as a potential transcriptional activator for fibroblast growth factor-4 (FGF-4) in human breast cancer cells.Biochem J. 2003; 375: 199-205Crossref PubMed Scopus (55) Google Scholar, 34Corcoran L.M. Karvelas M. Oct-2 is required early in T cell-independent B cell activation for G1 progression and for proliferation.Immunity. 1994; 1: 635-645Abstract Full Text PDF PubMed Scopus (100) Google Scholar Published hepatocyte chromatin immunoprecipitation (ChIP) assays show that the HNF6 transcription factor occupied endogenous promoters of the cell cycle regulatory genes Cdc25A, Cdk2, and E2F1,35Odom D.T. Zizlsperger N. Gordon D.B. Bell G.W. Rinaldi N.J. Murray H.L. Volkert T.L. Schreiber J. Rolfe P.A. Gifford D.K. Fraenkel E. Bell G.I. Young R.A. Control of pancreas and liver gene expression by HNF transcription factors.Science. 2004; 303: 1378-1381Crossref PubMed Scopus (1059) Google Scholar suggesting the hypothesis that HNF6 regulates hepatocyte proliferation during liver regeneration. Mouse genetic studies showed that Hnf6−/− embryos fail to develop a functional endocrine pancreas, a gallbladder, and extrahepatic bile ducts.36Clotman F. Lannoy V.J. Reber M. Cereghini S. Cassiman D. Jacquemin P. Roskams T. Rousseau G.G. Lemaigre F.P. The onecut transcription factor HNF6 is required for normal development of the biliary tract.Development. 2002; 129: 1819-1828Crossref PubMed Google Scholar, 37Jacquemin P. Durviaux S.M. Jensen J. Godfraind C. Gradwohl G. Guillemot F. Madsen O.D. Carmeliet P. Dewerchin M. Collen D. Rousseau G.G. Lemaigre F.P. Transcription factor hepatocyte nuclear factor 6 regulates pancreatic endocrine cell differentiation and controls expression of the proendocrine gene ngn3.Mol Cell Biol. 2000; 20: 4445-4454Crossref PubMed Scopus (275) Google Scholar, 38Jacquemin P. Lemaigre F.P. Rousseau G.G. The Onecut transcription factor HNF-6 (OC-1) is required for timely specification of the pancreas and acts upstream of Pdx-1 in the specification cascade.Dev Biol. 2003; 258: 105-116Crossref PubMed Scopus (155) Google Scholar Interestingly, similar to the Foxm1 transcription factor, HNF6 is also required for development of intrahepatic bile ducts in the developing liver.36Clotman F. Lannoy V.J. Reber M. Cereghini S. Cassiman D. Jacquemin P. Roskams T. Rousseau G.G. Lemaigre F.P. The onecut transcription factor HNF6 is required for normal development of the biliary tract.Development. 2002; 129: 1819-1828Crossref PubMed Google Scholar In the adult mouse liver, HNF6 protein continues to be expressed in hepatocytes, with increased levels of the HNF6 protein in the biliary epithelial cells.36Clotman F. Lannoy V.J. Reber M. Cereghini S. Cassiman D. Jacquemin P. Roskams T. Rousseau G.G. Lemaigre F.P. The onecut transcription factor HNF6 is required for normal development of the biliary tract.Development. 2002; 129: 1819-1828Crossref PubMed Google Scholar, 39Holterman A.X. Tan Y. Kim W. Yoo K.W. Costa R.H. Diminished hepatic expression of the HNF-6 transcription factor during bile duct obstruction.Hepatology. 2002; 35: 1392-1399Crossref PubMed Scopus (22) Google Scholar The HNF6 transcription factor regulates the in vivo hepatic expression of the glucokinase,40Lannoy V.J. Decaux J.F. Pierreux C.E. Lemaigre F.P. Rousseau G.G. Liver glucokinase gene expression is controlled by the onecut transcription factor hepatocyte nuclear factor-6.Diabetologia. 2002; 45: 1136-1141Crossref PubMed Scopus (46) Google Scholar glucose transporter 2,41Tan Y. Adami G. Costa R.H. Maintaining HNF-6 expression prevents AdHNF3β. Mediated decrease in hepatic levels of Glut2 and glycogen.Hepatology. 2002; 35: 790-798Crossref PubMed Scopus (29) Google Scholar protein C,42Spek C.A. Lannoy V.J. Lemaigre F.P. Rousseau G.G. Bertina R.M. Reitsma P.H. Type I protein C deficiency caused by disruption of a hepatocyte nuclear factor (HNF)-6/HNF-1 binding site in the human protein C gene promoter.J Biol Chem. 1998; 273: 10168-10173Crossref PubMed Scopus (28) Google Scholar and cholesterol 7α-hydroxylase genes.43Wang M.H. Tan Y. Costa R.H. Holterman A.X.L. In vivo regulation of CYP7A1 by HNF-6 a novel mechanism for diminished CYP7A1 expression in biliary obstruction.Hepatology. 2004; 40: 600-608Crossref PubMed Scopus (18) Google Scholar HNF6 transcriptional activity requires an N-terminal STP box that is rich in serine, threonine, and proline residues, and the cut-homeodomain DBD sequences mediate recruitment of the adenosine 3′,5′-cyclic monophosphate response element binding protein (CBP) histone acetyltransferase.44Lannoy V.J. Rodolosse A. Pierreux C.E. Rousseau G.G. Lemaigre F.P. Transcriptional stimulation by hepatocyte nuclear factor-6. Target-specific recruitment of either CREB-binding protein (CBP) or p300/CBP-associated factor (p/CAF).J Biol Chem. 2000; 275: 22098-22103Crossref PubMed Scopus (48) Google Scholar Published cotransfection studies showed that formation of complexes between the DBDs of the HNF6 and Foxa2 transcription factors resulted in Foxa2 transcriptional activity through recruitment of the CBP coactivator protein by the HNF6 cut-homeodomain sequences.45Rausa F. Tan Y. Costa R.H. Association between HNF-6 and FoxA2 DNA binding domains stimulates FoxA2 transcriptional activity but inhibits HNF-6 DNA binding.Mol Cell Biol. 2003; 23: 437-449Crossref PubMed Scopus (68) Google Scholar In this current study, mice were infected with adenovirus expressing HNF6 (AdHNF6) to increase hepatic expression of HNF6 during liver regeneration. Increased hepatic levels of HNF6 significantly stimulated the number of regenerating mouse hepatocytes entering S phase following partial hepatectomy. HNF6-mediated stimulation in hepatocyte S-phase progression was associated with increased expression of the hepatocyte mitogen TGF-α and cell cycle regulators cyclin D1, Cdk2, and the Foxm1 transcription factor. Cotransfection and ChIP assays showed that TGF-α, cyclin D1, and HNF6 promoters are direct transcriptional targets of HNF6 and that combining HNF6 and FoxM1b further stimulated transcription of the TGF-α promoter. We also show that HNF6 associates with FoxM1 protein to stimulate Foxm1 transcriptional activity in cotransfection assays. Furthermore, cotransfection and ChIP assays show that both Foxm1 and HNF6 proteins activate transcription of the endogenous HNF6 promoter region. These liver regeneration studies show for the first time that the liver-enriched HNF6 transcription factor is capable of stimulating proliferation of regenerating hepatocytes through transcriptional activation of cell cycle regulatory genes. Generation of the adenovirus containing the cytomegalovirus (CMV) promoter driving expression of the mouse HNF6 complementary DNA (cDNA) (AdHNF6) and adenovirus expressing the bacterial LacZ or β-galactosidase gene (AdLacZ) was described previously.41Tan Y. Adami G. Costa R.H. Maintaining HNF-6 expression prevents AdHNF3β. Mediated decrease in hepatic levels of Glut2 and glycogen.Hepatology. 2002; 35: 790-798Crossref PubMed Scopus (29) Google Scholar Recombinant adenoviruses were used to infect QBO-293 cells (Quantum Biotechnologies, Montreal, Canada), and cell lysates were harvested 72 hours after infection. Adenovirus particles were purified from this cell lysate by CsCl centrifugation and dialyzed to remove the CsCl as described previously.46Tan Y. Costa R.H. Kovesdi I. Reichel R.R. Adenovirus-mediated increase of HNF-3 levels stimulates transthyretin and sonic hedgehog expression, which is associated with F9 cell differentiation toward the visceral endoderm lineage.Gene Expr. 2001; 9: 237-248Crossref PubMed Scopus (29) Google Scholar, 47Tan Y. Hughes D.E. Wang X. Costa R.H. Adenovirus-mediated hepatic increase in HNF-3α or HNF-3α shows differences in levels of liver glycogen and gene expression.Hepatology. 2002; 35: 30-39Crossref PubMed Scopus (22) Google Scholar Two days before partial hepatectomy was performed, 2-month-old CD-1 mice were subjected to tail vein injection of 200 μL phosphate-buffered saline containing 1 × 1011Sherr C.J. Roberts J.M. CDK inhibitors positive and negative regulators of G1-phase progression.Genes Dev. 1999; 13: 1501-1512Crossref PubMed Scopus (5072) Google Scholar purified adenovirus particles (AdHNF6 or AdLacZ). Two days after infection, all of the CD-1 mice were subjected to partial hepatectomy to induce liver regeneration as described previously.22Ye H. Holterman A. Yoo K.W. Franks R.R. Costa R.H. Premature expression of the winged helix transcription factor HFH-11B in regenerating mouse liver accelerates hepatocyte entry into S-phase.Mol Cell Biol. 1999; 19: 8570-8580Crossref PubMed Scopus (165) Google Scholar, 23Wang X. Kiyokawa H. Dennewitz M.B. Costa R.H. The Forkhead Box m1b transcription factor is essential for hepatocyte DNA replication and mitosis during mouse liver regeneration.Proc Natl Acad Sci U S A. 2002; 99: 16881-16886Crossref PubMed Scopus (271) Google Scholar, 48Wang X. Krupczak-Hollis K. Tan Y. Dennewitz M.B. Adami G.R. Costa R.H. Increased hepatic Forkhead Box M1B (FoxM1B) levels in old-aged mice stimulated liver regeneration through diminished p27Kip1 protein levels and increased Cdc25B expression.J Biol Chem. 2002; 277: 44310-44316Crossref PubMed Scopus (125) Google Scholar Three mice at each time point were killed using co2 asphyxiation at 24, 32, 36, 40, 44, or 48 hours following partial hepatectomy. An intraperitoneal injection of a phosphate-buffered saline solution containing 10 mg/mL bromodeoxyuridine (BrdU, 50 mg/g body wt; Sigma Chemical Co, St Louis, MO) was administered 2 hours before harvesting the remnant regenerating liver. The regenerating livers were harvested and divided into 3 portions: one to isolate total RNA,22Ye H. Holterman A. Yoo K.W. Franks R.R. Costa R.H. Premature expression of the winged helix transcription factor HFH-11B in regenerating mouse liver accelerates hepatocyte entry into S-phase.Mol Cell Biol. 1999; 19: 8570-8580Crossref PubMed Scopus (165) Google Scholar one to isolate total protein extract,49Rausa F.M. Tan Y. Zhou H. Yoo K. Stolz D.B. Watkins S. Franks R.R. Unterman T.G. Costa R.H. Elevated levels of HNF-3α in mouse hepatocytes influence expression of genes involved in bile acid and glucose homeostasis.Mol Cell Biol. 2000; 20: 8264-8282Crossref PubMed Scopus (98) Google Scholar and one for paraffin embedding.23Wang X. Kiyokawa H. Dennewitz M.B. Costa R.H. The Forkhead Box m1b transcription factor is essential for hepatocyte DNA replication and mitosis during mouse liver regeneration.Proc Natl Acad Sci U S A. 2002; 99: 16881-16886Crossref PubMed Scopus (271) Google Scholar, 48Wang X. Krupczak-Hollis K. Tan Y. Dennewitz M.B. Adami G.R. Costa R.H. Increased hepatic Forkhead Box M1B (FoxM1B) levels in old-aged mice stimulated liver regeneration through diminished p27Kip1 protein levels and increased Cdc25B expression.J Biol Chem. 2002; 277: 44310-44316Crossref PubMed Scopus (125) Google Scholar Determination of the number of hepatocytes undergoing DNA synthesis was performed by monoclonal antibody detection of BrdU incorporation (Roche, Mannheim, Germany) of regenerating liver (5-μm paraffin sections) using the microwave antigen retrieval method described previously.22Ye H. Holterman A. Yoo K.W. Franks R.R. Costa R.H. Premature expression of the winged helix transcription factor HFH-11B in regenerating mouse liver accelerates hepatocyte entry into S-phase.Mol Cell Biol. 1999; 19: 8570-8580Crossref PubMed Scopus (165) Google Scholar Using 3 regenerating livers per time point, we counted the number of BrdU-positive nuclei per 1000 hepatocytes to calculate the mean number of BrdU-positive cells (±SD) as described previously.22Ye H. Holterman A. Yoo K.W. Franks R.R. Costa R.H. Premature expression of the winged helix transcription factor HFH-11B in regenerating mouse liver accelerates hepatocyte entry into S-phase.Mol Cell Biol. 1999; 19: 8570-8580Crossref PubMed Scopus (165) Google Scholar Three regenerating liver sections per time point (36, 40, 44, and 48 hours after partial hepatectomy) were stained with H&E and examined for mitotic" @default.
• W2012053529 created "2016-06-24" @default.
• W2012053529 creator A5009689031 @default.
• W2012053529 creator A5024410377 @default.
• W2012053529 creator A5045158010 @default.
• W2012053529 creator A5055630098 @default.
• W2012053529 date "2006-04-01" @default.
• W2012053529 modified "2023-10-14" @default.
• W2012053529 title "Increased Expression of Hepatocyte Nuclear Factor 6 Stimulates Hepatocyte Proliferation During Mouse Liver Regeneration" @default.
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