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. 1999 Feb;52(1):19–24. doi: 10.1136/mp.52.1.19

Liver enriched transcription factors and differentiation of hepatocellular carcinoma.

Y Hayashi 1, W Wang 1, T Ninomiya 1, H Nagano 1, K Ohta 1, H Itoh 1
PMCID: PMC395665  PMID: 10439834

Abstract

The development of a complex organism relies on the precise temporal and spacial expression of its genome in many different cell types. The unique phenotype of hepatocytes arises from the expression of genes in a liver specific fashion, which is controlled primarily at the level of mRNA synthesis. By analysing DNA sequences implicated in liver specific transcription, it has been possible to identify members of the nuclear proteins, such as the liver enriched transactivating factors, hepatic nuclear factor 1(HNF-1), HNF-3, HNF-4, HNF-6, CCAAT/enhancer binding protein (C/EBP), and D binding protein (DBP), which are key elements in the liver specific transcriptional regulation of genes. Each of these factors is characterised by DNA binding domains that bind to unique DNA sequences (cis-acting factors) in the promoter and enhancer regions of genes expressed in terminally differentiated hepatocytes (such as, albumin, alpha 1-antitrypsin, transthyretin, alpha-fetoprotein). The determination of the tissue distribution of these factors and analysis of their hierarchical relations has led to the hypothesis that the cooperation of liver enriched transcription factors with the ubiquitous transactivating factors is necessary, and possibly even sufficient, for the maintenance of liver specific gene transcription. With the increase in information about transcriptional regulation, it should be possible to evaluate fully the clinicopathological usefulness of transcription factors in the diagnosis and treatment of hepatocellular carcinoma.

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Selected References

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  1. Akira S., Isshiki H., Sugita T., Tanabe O., Kinoshita S., Nishio Y., Nakajima T., Hirano T., Kishimoto T. A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. EMBO J. 1990 Jun;9(6):1897–1906. doi: 10.1002/j.1460-2075.1990.tb08316.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ang S. L., Wierda A., Wong D., Stevens K. A., Cascio S., Rossant J., Zaret K. S. The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins. Development. 1993 Dec;119(4):1301–1315. doi: 10.1242/dev.119.4.1301. [DOI] [PubMed] [Google Scholar]
  3. Birkenmeier E. H., Gwynn B., Howard S., Jerry J., Gordon J. I., Landschulz W. H., McKnight S. L. Tissue-specific expression, developmental regulation, and genetic mapping of the gene encoding CCAAT/enhancer binding protein. Genes Dev. 1989 Aug;3(8):1146–1156. doi: 10.1101/gad.3.8.1146. [DOI] [PubMed] [Google Scholar]
  4. Cao Z., Umek R. M., McKnight S. L. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev. 1991 Sep;5(9):1538–1552. doi: 10.1101/gad.5.9.1538. [DOI] [PubMed] [Google Scholar]
  5. Caron J. M. Induction of albumin gene transcription in hepatocytes by extracellular matrix proteins. Mol Cell Biol. 1990 Mar;10(3):1239–1243. doi: 10.1128/mcb.10.3.1239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cereghini S., Blumenfeld M., Yaniv M. A liver-specific factor essential for albumin transcription differs between differentiated and dedifferentiated rat hepatoma cells. Genes Dev. 1988 Aug;2(8):957–974. doi: 10.1101/gad.2.8.957. [DOI] [PubMed] [Google Scholar]
  7. Cereghini S. Liver-enriched transcription factors and hepatocyte differentiation. FASEB J. 1996 Feb;10(2):267–282. [PubMed] [Google Scholar]
  8. Cereghini S., Ott M. O., Power S., Maury M. Expression patterns of vHNF1 and HNF1 homeoproteins in early postimplantation embryos suggest distinct and sequential developmental roles. Development. 1992 Nov;116(3):783–797. doi: 10.1242/dev.116.3.783. [DOI] [PubMed] [Google Scholar]
  9. Cereghini S., Yaniv M., Cortese R. Hepatocyte dedifferentiation and extinction is accompanied by a block in the synthesis of mRNA coding for the transcription factor HNF1/LFB1. EMBO J. 1990 Jul;9(7):2257–2263. doi: 10.1002/j.1460-2075.1990.tb07396.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chang H. K., Wang B. Y., Yuh C. H., Wei C. L., Ting L. P. A liver-specific nuclear factor interacts with the promoter region of the large surface protein gene of human hepatitis B virus. Mol Cell Biol. 1989 Nov;9(11):5189–5197. doi: 10.1128/mcb.9.11.5189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Clairmont A., Ebert T., Weber H., Zoidl C., Eickelmann P., Schulz W. A., Sies H., Ryffel G. U. Lowered amounts of the tissue-specific transcription factor LFB1 (HNF1) correlate with decreased levels of glutathione S-transferase alpha messenger RNA in human renal cell carcinoma. Cancer Res. 1994 Mar 1;54(5):1319–1323. [PubMed] [Google Scholar]
  12. Costa R. H., Grayson D. R., Darnell J. E., Jr Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes. Mol Cell Biol. 1989 Apr;9(4):1415–1425. doi: 10.1128/mcb.9.4.1415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Costa R. H., Grayson D. R., Darnell J. E., Jr Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes. Mol Cell Biol. 1989 Apr;9(4):1415–1425. doi: 10.1128/mcb.9.4.1415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Costa R. H., Lai E., Grayson D. R., Darnell J. E., Jr The cell-specific enhancer of the mouse transthyretin (prealbumin) gene binds a common factor at one site and a liver-specific factor(s) at two other sites. Mol Cell Biol. 1988 Jan;8(1):81–90. doi: 10.1128/mcb.8.1.81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Courtois G., Baumhueter S., Crabtree G. R. Purified hepatocyte nuclear factor 1 interacts with a family of hepatocyte-specific promoters. Proc Natl Acad Sci U S A. 1988 Nov;85(21):7937–7941. doi: 10.1073/pnas.85.21.7937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Courtois G., Morgan J. G., Campbell L. A., Fourel G., Crabtree G. R. Interaction of a liver-specific nuclear factor with the fibrinogen and alpha 1-antitrypsin promoters. Science. 1987 Oct 30;238(4827):688–692. doi: 10.1126/science.3499668. [DOI] [PubMed] [Google Scholar]
  17. De Simone V., De Magistris L., Lazzaro D., Gerstner J., Monaci P., Nicosia A., Cortese R. LFB3, a heterodimer-forming homeoprotein of the LFB1 family, is expressed in specialized epithelia. EMBO J. 1991 Jun;10(6):1435–1443. doi: 10.1002/j.1460-2075.1991.tb07664.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. DiPersio C. M., Jackson D. A., Zaret K. S. The extracellular matrix coordinately modulates liver transcription factors and hepatocyte morphology. Mol Cell Biol. 1991 Sep;11(9):4405–4414. doi: 10.1128/mcb.11.9.4405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Eguchi H., Westin S., Ström A., Gustafsson J. A., Zaphiropoulos P. G. Gene structure and expression of the rat cytochrome P450IIC13, a polymorphic, male-specific cytochrome in the P450IIC subfamily. Biochemistry. 1991 Nov 12;30(45):10844–10849. doi: 10.1021/bi00109a006. [DOI] [PubMed] [Google Scholar]
  20. Eisenmann D. M., Kim S. K. Signal transduction and cell fate specification during Caenorhabditis elegans vulval development. Curr Opin Genet Dev. 1994 Aug;4(4):508–516. doi: 10.1016/0959-437x(94)90065-b. [DOI] [PubMed] [Google Scholar]
  21. Ellenberger T. E., Brandl C. J., Struhl K., Harrison S. C. The GCN4 basic region leucine zipper binds DNA as a dimer of uninterrupted alpha helices: crystal structure of the protein-DNA complex. Cell. 1992 Dec 24;71(7):1223–1237. doi: 10.1016/s0092-8674(05)80070-4. [DOI] [PubMed] [Google Scholar]
  22. Falvey E., Marcacci L., Schibler U. DNA-binding specificity of PAR and C/EBP leucine zipper proteins: a single amino acid substitution in the C/EBP DNA-binding domain confers PAR-like specificity to C/EBP. Biol Chem. 1996 Dec;377(12):797–809. [PubMed] [Google Scholar]
  23. Frain M., Swart G., Monaci P., Nicosia A., Stämpfli S., Frank R., Cortese R. The liver-specific transcription factor LF-B1 contains a highly diverged homeobox DNA binding domain. Cell. 1989 Oct 6;59(1):145–157. doi: 10.1016/0092-8674(89)90877-5. [DOI] [PubMed] [Google Scholar]
  24. Freytag S. O., Paielli D. L., Gilbert J. D. Ectopic expression of the CCAAT/enhancer-binding protein alpha promotes the adipogenic program in a variety of mouse fibroblastic cells. Genes Dev. 1994 Jul 15;8(14):1654–1663. doi: 10.1101/gad.8.14.1654. [DOI] [PubMed] [Google Scholar]
  25. Friedman A. D., Landschulz W. H., McKnight S. L. CCAAT/enhancer binding protein activates the promoter of the serum albumin gene in cultured hepatoma cells. Genes Dev. 1989 Sep;3(9):1314–1322. doi: 10.1101/gad.3.9.1314. [DOI] [PubMed] [Google Scholar]
  26. Hardon E. M., Frain M., Paonessa G., Cortese R. Two distinct factors interact with the promoter regions of several liver-specific genes. EMBO J. 1988 Jun;7(6):1711–1719. doi: 10.1002/j.1460-2075.1988.tb03000.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hoshizaki D. K., Blackburn T., Price C., Ghosh M., Miles K., Ragucci M., Sweis R. Embryonic fat-cell lineage in Drosophila melanogaster. Development. 1994 Sep;120(9):2489–2499. doi: 10.1242/dev.120.9.2489. [DOI] [PubMed] [Google Scholar]
  28. Jackson D. A., Rowader K. E., Stevens K., Jiang C., Milos P., Zaret K. S. Modulation of liver-specific transcription by interactions between hepatocyte nuclear factor 3 and nuclear factor 1 binding DNA in close apposition. Mol Cell Biol. 1993 Apr;13(4):2401–2410. doi: 10.1128/mcb.13.4.2401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Johnson P. F. Identification of C/EBP basic region residues involved in DNA sequence recognition and half-site spacing preference. Mol Cell Biol. 1993 Nov;13(11):6919–6930. doi: 10.1128/mcb.13.11.6919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Johnson P. F., Landschulz W. H., Graves B. J., McKnight S. L. Identification of a rat liver nuclear protein that binds to the enhancer core element of three animal viruses. Genes Dev. 1987 Apr;1(2):133–146. doi: 10.1101/gad.1.2.133. [DOI] [PubMed] [Google Scholar]
  31. Kalkuhl A., Kaestner K., Buchmann A., Schwarz M. Expression of hepatocyte-enriched nuclear transcription factors in mouse liver tumours. Carcinogenesis. 1996 Mar;17(3):609–612. doi: 10.1093/carcin/17.3.609. [DOI] [PubMed] [Google Scholar]
  32. Ktistaki E., Ktistakis N. T., Papadogeorgaki E., Talianidis I. Recruitment of hepatocyte nuclear factor 4 into specific intranuclear compartments depends on tyrosine phosphorylation that affects its DNA-binding and transactivation potential. Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9876–9880. doi: 10.1073/pnas.92.21.9876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Ktistaki E., Talianidis I. Modulation of hepatic gene expression by hepatocyte nuclear factor 1. Science. 1997 Jul 4;277(5322):109–112. doi: 10.1126/science.277.5322.109. [DOI] [PubMed] [Google Scholar]
  34. Kuo C. J., Conley P. B., Chen L., Sladek F. M., Darnell J. E., Jr, Crabtree G. R. A transcriptional hierarchy involved in mammalian cell-type specification. Nature. 1992 Jan 30;355(6359):457–461. doi: 10.1038/355457a0. [DOI] [PubMed] [Google Scholar]
  35. Lai E., Prezioso V. R., Smith E., Litvin O., Costa R. H., Darnell J. E., Jr HNF-3A, a hepatocyte-enriched transcription factor of novel structure is regulated transcriptionally. Genes Dev. 1990 Aug;4(8):1427–1436. doi: 10.1101/gad.4.8.1427. [DOI] [PubMed] [Google Scholar]
  36. Lai E., Prezioso V. R., Tao W. F., Chen W. S., Darnell J. E., Jr Hepatocyte nuclear factor 3 alpha belongs to a gene family in mammals that is homologous to the Drosophila homeotic gene fork head. Genes Dev. 1991 Mar;5(3):416–427. doi: 10.1101/gad.5.3.416. [DOI] [PubMed] [Google Scholar]
  37. Landry C., Clotman F., Hioki T., Oda H., Picard J. J., Lemaigre F. P., Rousseau G. G. HNF-6 is expressed in endoderm derivatives and nervous system of the mouse embryo and participates to the cross-regulatory network of liver-enriched transcription factors. Dev Biol. 1997 Dec 15;192(2):247–257. doi: 10.1006/dbio.1997.8757. [DOI] [PubMed] [Google Scholar]
  38. Landschulz W. H., Johnson P. F., Adashi E. Y., Graves B. J., McKnight S. L. Isolation of a recombinant copy of the gene encoding C/EBP. Genes Dev. 1988 Jul;2(7):786–800. doi: 10.1101/gad.2.7.786. [DOI] [PubMed] [Google Scholar]
  39. Landschulz W. H., Johnson P. F., McKnight S. L. The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. Science. 1988 Jun 24;240(4860):1759–1764. doi: 10.1126/science.3289117. [DOI] [PubMed] [Google Scholar]
  40. Lavery D. J., Schibler U. Circadian transcription of the cholesterol 7 alpha hydroxylase gene may involve the liver-enriched bZIP protein DBP. Genes Dev. 1993 Oct;7(10):1871–1884. doi: 10.1101/gad.7.10.1871. [DOI] [PubMed] [Google Scholar]
  41. Lemaigre 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 Sep 3;93(18):9460–9464. doi: 10.1073/pnas.93.18.9460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Lichtsteiner S., Wuarin J., Schibler U. The interplay of DNA-binding proteins on the promoter of the mouse albumin gene. Cell. 1987 Dec 24;51(6):963–973. doi: 10.1016/0092-8674(87)90583-6. [DOI] [PubMed] [Google Scholar]
  43. Lin F. T., Lane M. D. Antisense CCAAT/enhancer-binding protein RNA suppresses coordinate gene expression and triglyceride accumulation during differentiation of 3T3-L1 preadipocytes. Genes Dev. 1992 Apr;6(4):533–544. doi: 10.1101/gad.6.4.533. [DOI] [PubMed] [Google Scholar]
  44. Lin F. T., Lane M. D. CCAAT/enhancer binding protein alpha is sufficient to initiate the 3T3-L1 adipocyte differentiation program. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8757–8761. doi: 10.1073/pnas.91.19.8757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Maniatis T., Goodbourn S., Fischer J. A. Regulation of inducible and tissue-specific gene expression. Science. 1987 Jun 5;236(4806):1237–1245. doi: 10.1126/science.3296191. [DOI] [PubMed] [Google Scholar]
  46. Mehta R. The potential for the use of cell proliferation and oncogene expression as intermediate markers during liver carcinogenesis. Cancer Lett. 1995 Jun 29;93(1):85–102. doi: 10.1016/0304-3835(95)03790-4. [DOI] [PubMed] [Google Scholar]
  47. Mendel D. B., Hansen L. P., Graves M. K., Conley P. B., Crabtree G. R. HNF-1 alpha and HNF-1 beta (vHNF-1) share dimerization and homeo domains, but not activation domains, and form heterodimers in vitro. Genes Dev. 1991 Jun;5(6):1042–1056. doi: 10.1101/gad.5.6.1042. [DOI] [PubMed] [Google Scholar]
  48. Mietus-Snyder M., Sladek F. M., Ginsburg G. S., Kuo C. F., Ladias J. A., Darnell J. E., Jr, Karathanasis S. K. Antagonism between apolipoprotein AI regulatory protein 1, Ear3/COUP-TF, and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells. Mol Cell Biol. 1992 Apr;12(4):1708–1718. doi: 10.1128/mcb.12.4.1708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Mischoulon D., Rana B., Bucher N. L., Farmer S. R. Growth-dependent inhibition of CCAAT enhancer-binding protein (C/EBP alpha) gene expression during hepatocyte proliferation in the regenerating liver and in culture. Mol Cell Biol. 1992 Jun;12(6):2553–2560. doi: 10.1128/mcb.12.6.2553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Mizuguchi T., Mitaka T., Hirata K., Oda H., Mochizuki Y. Alteration of expression of liver-enriched transcription factors in the transition between growth and differentiation of primary cultured rat hepatocytes. J Cell Physiol. 1998 Mar;174(3):273–284. doi: 10.1002/(SICI)1097-4652(199803)174:3<273::AID-JCP1>3.0.CO;2-L. [DOI] [PubMed] [Google Scholar]
  51. Monaghan A. P., Kaestner K. H., Grau E., Schütz G. Postimplantation expression patterns indicate a role for the mouse forkhead/HNF-3 alpha, beta and gamma genes in determination of the definitive endoderm, chordamesoderm and neuroectoderm. Development. 1993 Nov;119(3):567–578. doi: 10.1242/dev.119.3.567. [DOI] [PubMed] [Google Scholar]
  52. Mueller C. R., Maire P., Schibler U. DBP, a liver-enriched transcriptional activator, is expressed late in ontogeny and its tissue specificity is determined posttranscriptionally. Cell. 1990 Apr 20;61(2):279–291. doi: 10.1016/0092-8674(90)90808-r. [DOI] [PubMed] [Google Scholar]
  53. Nakano M., Saito A., Yamamoto M., Doi M., Takasaki K. Stromal and blood vessel wall invasion in well-differentiated hepatocellular carcinoma. Liver. 1997 Feb;17(1):41–46. doi: 10.1111/j.1600-0676.1997.tb00777.x. [DOI] [PubMed] [Google Scholar]
  54. Nakashima O., Sugihara S., Kage M., Kojiro M. Pathomorphologic characteristics of small hepatocellular carcinoma: a special reference to small hepatocellular carcinoma with indistinct margins. Hepatology. 1995 Jul;22(1):101–105. [PubMed] [Google Scholar]
  55. Natsuka S., Akira S., Nishio Y., Hashimoto S., Sugita T., Isshiki H., Kishimoto T. Macrophage differentiation-specific expression of NF-IL6, a transcription factor for interleukin-6. Blood. 1992 Jan 15;79(2):460–466. [PubMed] [Google Scholar]
  56. Ninomiya T., Hayashi Y., Saijoh K., Ohta K., Yoon S., Nakabayashi H., Tamaoki T., Kasuga M., Itoh H. Expression ratio of hepatocyte nuclear factor-1 to variant hepatocyte nuclear factor-1 in differentiation of hepatocellular carcinoma and hepatoblastoma. J Hepatol. 1996 Oct;25(4):445–453. doi: 10.1016/s0168-8278(96)80203-0. [DOI] [PubMed] [Google Scholar]
  57. Pani L., Overdier D. G., Porcella A., Qian X., Lai E., Costa R. H. Hepatocyte nuclear factor 3 beta contains two transcriptional activation domains, one of which is novel and conserved with the Drosophila fork head protein. Mol Cell Biol. 1992 Sep;12(9):3723–3732. doi: 10.1128/mcb.12.9.3723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Pani L., Quian X. B., Clevidence D., Costa R. H. The restricted promoter activity of the liver transcription factor hepatocyte nuclear factor 3 beta involves a cell-specific factor and positive autoactivation. Mol Cell Biol. 1992 Feb;12(2):552–562. doi: 10.1128/mcb.12.2.552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Peterson R. S., Clevidence D. E., Ye H., Costa R. H. Hepatocyte nuclear factor-3 alpha promoter regulation involves recognition by cell-specific factors, thyroid transcription factor-1, and autoactivation. Cell Growth Differ. 1997 Jan;8(1):69–82. [PubMed] [Google Scholar]
  60. Rausa 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-3 beta in the developing murine liver and pancreas. Dev Biol. 1997 Dec 15;192(2):228–246. doi: 10.1006/dbio.1997.8744. [DOI] [PubMed] [Google Scholar]
  61. Rey-Campos J., Chouard T., Yaniv M., Cereghini S. vHNF1 is a homeoprotein that activates transcription and forms heterodimers with HNF1. EMBO J. 1991 Jun;10(6):1445–1457. doi: 10.1002/j.1460-2075.1991.tb07665.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Rim K. S., Sakamoto M., Watanabe H., Matsuno Y., Nakanishi Y., Mukai K., Hirohashi S. Pathology and DNA cytophotometry of small hepatocellular carcinoma with a nodule-in-nodule appearance--evidence for stepwise progression of hepatocellular carcinoma. Jpn J Clin Oncol. 1993 Feb;23(1):26–33. [PubMed] [Google Scholar]
  63. Samadani U., Costa R. H. The transcriptional activator hepatocyte nuclear factor 6 regulates liver gene expression. Mol Cell Biol. 1996 Nov;16(11):6273–6284. doi: 10.1128/mcb.16.11.6273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Samuelsson L., Strömberg K., Vikman K., Bjursell G., Enerbäck S. The CCAAT/enhancer binding protein and its role in adipocyte differentiation: evidence for direct involvement in terminal adipocyte development. EMBO J. 1991 Dec;10(12):3787–3793. doi: 10.1002/j.1460-2075.1991.tb04948.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Screpanti I., Romani L., Musiani P., Modesti A., Fattori E., Lazzaro D., Sellitto C., Scarpa S., Bellavia D., Lattanzio G. Lymphoproliferative disorder and imbalanced T-helper response in C/EBP beta-deficient mice. EMBO J. 1995 May 1;14(9):1932–1941. doi: 10.1002/j.1460-2075.1995.tb07185.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Späth G. F., Weiss M. C. Hepatocyte nuclear factor 4 expression overcomes repression of the hepatic phenotype in dedifferentiated hepatoma cells. Mol Cell Biol. 1997 Apr;17(4):1913–1922. doi: 10.1128/mcb.17.4.1913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Späth G. F., Weiss M. C. Hepatocyte nuclear factor 4 provokes expression of epithelial marker genes, acting as a morphogen in dedifferentiated hepatoma cells. J Cell Biol. 1998 Feb 23;140(4):935–946. doi: 10.1083/jcb.140.4.935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Stumpf H., Senkel S., Rabes H. M., Ryffel G. U. The DNA binding activity of the liver transcription factors LFB1 (HNF1) and HNF4 varies coordinately in rat hepatocellular carcinoma. Carcinogenesis. 1995 Jan;16(1):143–145. doi: 10.1093/carcin/16.1.143. [DOI] [PubMed] [Google Scholar]
  69. Tanaka T., Akira S., Yoshida K., Umemoto M., Yoneda Y., Shirafuji N., Fujiwara H., Suematsu S., Yoshida N., Kishimoto T. Targeted disruption of the NF-IL6 gene discloses its essential role in bacteria killing and tumor cytotoxicity by macrophages. Cell. 1995 Jan 27;80(2):353–361. doi: 10.1016/0092-8674(95)90418-2. [DOI] [PubMed] [Google Scholar]
  70. Timchenko N. A., Wilde M., Nakanishi M., Smith J. R., Darlington G. J. CCAAT/enhancer-binding protein alpha (C/EBP alpha) inhibits cell proliferation through the p21 (WAF-1/CIP-1/SDI-1) protein. Genes Dev. 1996 Apr 1;10(7):804–815. doi: 10.1101/gad.10.7.804. [DOI] [PubMed] [Google Scholar]
  71. Tsutsumi K., Ito K., Ishikawa K. Developmental appearance of transcription factors that regulate liver-specific expression of the aldolase B gene. Mol Cell Biol. 1989 Nov;9(11):4923–4931. doi: 10.1128/mcb.9.11.4923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Umek R. M., Friedman A. D., McKnight S. L. CCAAT-enhancer binding protein: a component of a differentiation switch. Science. 1991 Jan 18;251(4991):288–292. doi: 10.1126/science.1987644. [DOI] [PubMed] [Google Scholar]
  73. Viollet B., Kahn A., Raymondjean M. Protein kinase A-dependent phosphorylation modulates DNA-binding activity of hepatocyte nuclear factor 4. Mol Cell Biol. 1997 Aug;17(8):4208–4219. doi: 10.1128/mcb.17.8.4208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Wang W., Hayashi Y., Ninomiya T., Ohta K., Nakabayashi H., Tamaoki T., Itoh H. Expression of HNF-1 alpha and HNF-1 beta in various histological differentiations of hepatocellular carcinoma. J Pathol. 1998 Mar;184(3):272–278. doi: 10.1002/(SICI)1096-9896(199803)184:3<272::AID-PATH4>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
  75. Watkins P. J., Condreay J. P., Huber B. E., Jacobs S. J., Adams D. J. Impaired proliferation and tumorigenicity induced by CCAAT/enhancer-binding protein. Cancer Res. 1996 Mar 1;56(5):1063–1067. [PubMed] [Google Scholar]
  76. Weinstein D. C., Ruiz i Altaba A., Chen W. S., Hoodless P., Prezioso V. R., Jessell T. M., Darnell J. E., Jr The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo. Cell. 1994 Aug 26;78(4):575–588. doi: 10.1016/0092-8674(94)90523-1. [DOI] [PubMed] [Google Scholar]
  77. Xanthopoulos K. G., Prezioso V. R., Chen W. S., Sladek F. M., Cortese R., Darnell J. E., Jr The different tissue transcription patterns of genes for HNF-1, C/EBP, HNF-3, and HNF-4, protein factors that govern liver-specific transcription. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3807–3811. doi: 10.1073/pnas.88.9.3807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Zhang D. E., Zhang P., Wang N. D., Hetherington C. J., Darlington G. J., Tenen D. G. Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):569–574. doi: 10.1073/pnas.94.2.569. [DOI] [PMC free article] [PubMed] [Google Scholar]

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