UCR

Cell Biology and Neuroscience



Frances Sladek


Frances Sladek
Phone: (951) 827-2264
Fax: (951) 827-3087
Office Location: 2115 Biological Sciences
Office Hours:
Email: frances.sladek@ucr.edu

Frances M. Sladek

Professor of Cell Biology & Toxicologist
PhD, Yale University, 1988

Biography

Sladek Lab

We use the whole gamut of biological techniques -- molecular, cellular, biochemical, proteomic and genomic -- 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 also a highly conserved member of the nuclear receptor super family of ligand-dependent transcription factors.




Figure 1. Hepatocyte nuclear factor (HNF)4a and human disease.The relationship between HNF4a, select target genes and human diseases is shown. Shaded box, direct connection to diseases indicated; open box, possible connection.
Figure 2. 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.

Publications

  • Yang C, Bolotin E, Jiang T, Sladek FM, Martinez E. Prevalence of the initiator over the TATA box in human and yeast genes and identification of DNA motifs enriched in human TATA-less core promoters. Gene. 2006 Oct 10; [Epub ahead of print] PMID: 17123746 [PubMed - as supplied by publisher]
  • Maeda Y, Hwang-Verslues WW, Wei G, Fukazawa T, Durbin ML, Owen LB, Liu X, Sladek FM. Tumour suppressor p53 down-regulates the expression of the human hepatocyte nuclear factor 4alpha (HNF4alpha) gene. Biochem J. 2006 Dec 1;400(2):303-13. PMID: 16895524 [PubMed - in process]
  • Battle MA, Konopka G, Parviz F, Gaggl AL, Yang C, Sladek FM, Duncan SA. Hepatocyte nuclear factor 4{alpha} orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver. Proc Natl Acad Sci U S A. 2006 May 30;103(22):8419-24. Epub 2006 May 19.PMID: 16714383 [PubMed - in process]
  • Garrison WD, Battle MA, Yang C, Kaestner KH, Sladek FM, Duncan SA. Hepatocyte nuclear factor 4alpha is essential for embryonic development of the mouse colon. Gastroenterology. 2006 Apr;130(4):1207-20. PMID: 16618389 [PubMed - indexed for MEDLINE]
  • Zhang Y, Lee TS, Kolb EM, Sun K, Lu X, Sladek FM, Kassab GS, Garland T Jr,Shyy JY. AMP-activated protein kinase is involved in endothelial NO synthase activation in response to shear stress.Arterioscler Thromb Vasc Biol. 2006 Jun;26(6):1281-7. Epub 2006 Apr 6.PMID: 16601232 [PubMed - in process]
  • Miura A, Yamagata K, Kakei M, Hatakeyama H, Takahashi N, Fukui K, Nammo T,Yoneda K, Inoue Y, Sladek FM, Magnuson MA, Kasai H, Miyagawa J, Gonzalez FJ, Shimomura I. Hepatocyte nuclear factor-4alpha is essential for glucose-stimulated insulinsecretion by pancreatic beta-cells.J Biol Chem. 2006 Feb 24;281(8):5246-57. Epub 2005 Dec 23.PMID: 16377800 [PubMed - indexed for MEDLINE]
  • Ihara A, Yamagata K, Nammo T, Miura A, Yuan M, Tanaka T, Sladek FM, Matsuzawa Y, Miyagawa J, Shimomura I. Functional characterization of the HNF4alpha isoform (HNF4alpha8) expressed in pancreatic beta-cells.Biochem Biophys Res Commun. 2005 Apr 15;329(3):984-90.PMID: 15752752 [PubMed - indexed for MEDLINE]
  • 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. Ponder 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

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Cell Biology and Neuroscience
2109 Biological Science

David Eastmond: Chair of Cell Biology & Neurosience
Tel: (951) 827-4497
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E-mail: david.eastmond@ucr.edu

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