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Frances M. Sladek
Visit the Sladek Lab
Professor of Cell Biology & Toxicologist
2115 Biological Sciences Building
Department of Cell Biology & Neuroscience
Phone: 951-827-2264
FAX: 951-827-3087
(PhD, Yale University, 1988)
Email: frances.sladek@ucr.edu
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.
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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. |
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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. |
Representative Publications: (see Sladek Lab website
for complete list and links to 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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