Frances M. Sladek
Associate Professor of Cell Biology
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Molecular Endocrinology Biomedical Research
Ph.D.,Yale University, 1988
VOICE: 951-827-2264 |
We use molecular, cellular and biochemical techniques to decipher the molecular mechanism by which a certain liver-enriched transcription factor, hepatocyte nuclear factor 4 (HNF4), controls the expression of a variety of genes, including those involved in cholesterol, fatty acid and glucose metabolism as well as detoxification processes. HNF4 is essential for the development of a wide variety of organisms and has been directly linked to several human diseases, including diabetes, hemophilia and hepatitis B infections. HNF4 is a member of the nuclear receptor super family of ligand-dependent transcription factors.
Figure. Nuclear Receptor Subfamilies. Since HNF4 forms exclusively homodimers, is located only in the nucleus and binds DNA elements consisting of direct repeats, it defines a unique subfamily of nuclear receptors. This suggests that the mechanism of action of HNF4 is distinct from that of other receptors, which definitely appears to be the case. Adapted from Jiang et al., 1995, MCB 15: 5131-5143.
SELECTED PUBLICATIONS
T.Fukazawa*,Y.Maeda*,F.M. Sladek, and L.B. Owen-Schaub (2004). Development of a Cancer Targeted Tissue Specific Promoter System.Cancer Research,64: 363-369. *contributed equally.
F.M. Sladek (2003). Nuclear Receptors as Drug Targets: new Developments in Coregulators, orphan receptors and Major Therapeutic Areas. Expert Opinion Therapeutic Targets 7: 1-6
Q-J Li, S-H Yang, Y. Maeda, F.M. Sladek, A.D. Sharrocks, and M. Martins-Green (2003)MAP kinase phosphroylation-dependent activation of ELK-1leads to activation of the coactivator p300 EMBO, Vol. 22, No. 2 pp. 281-291.
F.M. Sladek (2002) Desperately seeking... something. Molecular Cell 10:(2) 219-221.
M. Torres-Padilla,F.M. Sladek and M. Weiss (2002) Developmentally regulated N-terminal variants of the nuclear receptor HNF4a mediate multiple interactions through coactivator and corepresor/HDAC complexes. Journal of Biological Chemistry, 277: 44677-44687
K. Ellrott, C.Yang, F.M. Sladek and T. Jiang (2002). Identifying transcription factor binding sites through Markov chain optimization. Bioinformatics,18,Suppl. 2, S1-S10.
Y. Maeda, C. Rachez, L. Hawel, III, C.V. Byus, L.P. Freedman and F.M. Sladek(2002). Polyamines modulate the interaction between nuclear receptors and DRIP205. Molecular Endocrinology 16:1502-10.
M.D. Ruse,Jr,M. Privalsky and F.M. Sladek(2002). Competitive Cofactor Recruitment by Orphan receptor HNF4a:modulation by the F domain.Molecular and Cellular Biology22:1626-1638.
Y. Maeda, S. D. Seidel, G. Wei, X. Liu and F. M. Sladek (2002). Repression of hepatocyte nuclear factor 4a by tumor suppressor p53: involvement of the ligand binding domain and histone deacetylase activity. (Molecular Endocrinology, 16:402-410).
B. Wang, S-R. Cai, C. Gao, F.M. Sladek, K.P. Parker (2001) Lipopolysaccharide results in a marked decrease in hepatocyte nuclear factor 4a in rat liver. Hepatology, 34: 979-989.
Sladek, F.M. and S. Seidel (2001) "Hepatocyte Nuclear Factor 4a" book chapter in Nuclear Receptors and Genetic Disease (ed.s T. P. Burris & E. McCabe, Academic Press, London).
Li, QJ., S. Vaingankar, F. M. Sladek, M. Martins-Green (2000) Novel Nuclear Target for Thrombin: Activation of the Elk1 Transcription Factor Leads to Chemokine Gene Expression. Blood 96: 3696-3706.
Bogan* A., Q. Dallas-Yang*, M.D. Ruse*, Jr., Y. Maeda, G. Jiang, L. Nepomuceno, T. Scanlan, F. E. Cohen and F.M. Sladek (2000) Analysis of Protein Dimerization and Ligand Binding of Orphan receptor HNF4a. Journal of Molecular Biology, 302: 831-851. *contributed equally
Sladek, F.M., M.D. Ruse, Jr., L. Nepomuceno, S.-M. Huang, M.R. Stallcup (1999) Modulation of Transcriptional Activation by a Splicing Variation in the F domain of Nuclear Receptor HNF4a, Molecular and Cellular Biology 19: 6509-6522.
Nuclear Receptor Nomenclature Committee (1999) A unified nomenclature system for the nuclear receptor superfamily, Cell 97: 161-163. (F.M. Sladek, endorsing author)
Sladek, F.M. Q. Dallas-Yang and L. Nepomuceno (1998) The MODY1 mutation in hepatocyte nuclear factor 4a still allows for dimerization in solution but causes abnormal sub cellular localization, Diabetes 47:985-990.
Dallas-Yang, G. Jiang and F.M. Sladek (1998) Avoidance of false positives in colony PCR, Biotechniques 24: 580-582.
Jiang, G., U. Lee and F.M. Sladek (1997) Proposed mechanism for the stabilization of nuclear receptor DNA binding via protein dimerization, Molecular and Cellular Biology 17:6546-6554.
Jiang, G.and F.M. Sladek (1997) The DNA binding domain of hepatocyte nuclear factor 4 (HNF-4) mediates cooperative, specific binding to DNA and heterodimerization with the retinoid X receptor a, Journal of Biological Chemistry 272: 1218-1225.
Jiang, G., L. Nepomuceno, Q. Yang and F.M. Sladek (1997) Serine/threonine phosphorylation of orphan receptor hepatocyte nuclear factor 4, Archives of Biochemistry and Biophysics 340:1-9.
Marten, N., F. M. Sladek, and D. S. Straus (1996) Effect of dietary protein restriction on liver transcription factors, Biochemical Journal 317: 361-370.
Hall, R.K., F. M. Sladek, and D. K. Granner (1995) The orphan receptors COUP-TF and HNF-4 serve as accessory factors required for induction of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids, Proc. Natl. Acad. Sci. USA 92: 412-416.
Jiang, G., L. Nepomuceno, K. Hopkins and F. M. Sladek (1995) Exclusive homodimerization of orphan receptor hepatocyte nuclear factor 4 defines a new subfamily of nuclear receptors, Molecular and Cellular Biology 15: 5131-5143.
Sladek, F.M. "Hepatocyte Nuclear factor 4 (HNF-4)" chapter in Liver Gene Expression, 1994 (ed.s F. Tronche, M. Yaniv, R.G. Landes Co., Austin, TX).
Zhong, W., F. M. Sladek, and J. E. Darnell, Jr. (1993) The expression pattern of a Drosophila homologue to the mouse transcription factor HNF-4 suggests a determinative role in gut formation. EMBO Journal Vol. 12, No. 2: 537-544.
Metzger, S., J. L. Halaas, J. L. Breslow and F. M. Sladek (1993) Orphan receptor HNF-4 and bZip protein C/EBPa bind to overlapping regions of the apolipoprotein B gene promoter and synergistically activate transcription, Journal of Biological Chemistry 268: 16831-16838.
Sladek, F.M. (1993) Orphan receptor HNF-4 and liver-specific gene expression. Receptor 3: 223-232.
Reijnen, M. J., F. M. Sladek, R. M. Bertina and P. H. Reitsma (1992) Disruption of a binding site for hepatocyte nuclear factor 4 results in Hemophilia B. Leyden, Proc. Natl. Acad. Sci. USA 89: 6300-6303.
Mietus-Snyder, M., F. M. Sladek, G. S. Ginsburg, C. F. Kuo, J.A.A. Ladias, J. E. Darnell, Jr. and S. K. Karathanasis (1992) Antagonism between apolipoportein AI regulatory protein 1, Ear3/Coup-TF and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells, Molecular and Cellular Biology 12: 1708-1718.
Sladek, F. M. and J. E. Darnell, Jr. (1992) Mechanisms of Liver-Specific Gene Expression, Current Opinions in Genetics and Development 2: 256-259.
Avraham, K. B., V. R. Prezioso, W. S. Chen, E. Lai, F. M. Sladek, W. Zhong, J. E. Darnell, Jr., N. A. Jenkins, and N. G. Copeland (1992) Murine Chromosomal Location of four Hepatocyte-Enriched Transcription Factors: HNF-3a, HNF-3b, HNF-3g, and HNF-4, Genomics 13: 264-268.
Kuo, C. J., P. B. Conley, L. Chen, F. M. Sladek, J. E. Darnell, Jr., and G. R. Crabtree (1992) A transcriptional hierarchy involved in mammalian cell-type specification, Nature 355: 457-461.
Herbst, R.S., U. Nielsch, F. Sladek, E. Lai, L.E. Babiss and J.E. Darnell, Jr. (1991) Decreased transcription factor concentration explains the limited hepatocyte-like transcription in hepatoma cells, New Biologist 3: 289-296.
Xanthopoulos, K.G., V.R. Prezioso, W.S. Chen, F.M. Sladek, R. Cortese and J.E. Darnell, Jr., (1991) 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. USA 88:3807-3811.
Sladek, F.M., W. Zhong, E. Lai and J.E. Darnell, Jr. (1990) Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily, Genes and Development 4: 2353-2365.
Sladek, F.M., A. Melian and P. Howard-Flanders (1989) Incision by UvrABC excinuclease is a step in the path to mutagenesis by psoralen crosslinks in Escherichia coli, Proc. Natl. Acad. Sci. USA 86, 3982-3986.
Sladek, F.M., M.M. Munn, W.D. Rupp and P. Howard-Flanders (1989) In Vitro Repair of Psoralen-DNA Crosslinks by RecA, UvrABC and the 5'-exonuclease of DNA Polymerase I, Journal of Biological Chemistry 264, 6755-6765.