Simon Williams, Ph.D.
Director of Basic Research, Southwest Cancer Treatment and Research Center
My interests in biology were stimulated in high school by a teacher who introduced me to the concepts of Genetics and that inspired me to study Genetics at Trinity College, Dublin. I then entered a Ph.D. program in Cellular and Molecular Biology at Roswell Park Memorial (now Cancer) Institute in Buffalo, New York and performed my thesis research in the laboratory of Alan Kinniburgh in the Department of Human Genetics. My thesis project focused on the regulation of the mouse apolipoprotein AIV gene in response to dietary lipids and this project was the origin of my interest in transcriptional regulation. I moved to the Frederick Cancer Research and Development Center in Frederick, Maryland for a postdoctoral position in Peter Johnson�s laboratory in 1990. Here, we isolated the various members of the CCAAT/enhancer binding protein family of transcription factors and began to determine their functions. I took one of these proteins, C/EBP? with me to Lubbock, when I started my laboratory in 1995 and the role of C/EBP? in neutrophil differentiation has been the focus of much of our work since then. A newer area of interest for the laboratory emerged from a collaboration with my wife, Kendra Rumbaugh from the Department of Surgery, where we investigate the interactions between host cells and pathogenic bacteria in burn wounds and cystic fibrosis.
1. Transcriptional regulation of neutrophil differentiation, applications in human leukemias
CCAAT/enhancer binding protein epsilon is a transcriptional regulator that is primarily expressed in, and required for terminal differentiation of neutrophils. Consequently, mutations in the cebpe gene in mice and humans result in immunodeficiency due to defects in innate immunity. In addition, loss of activity of C/EBPε and other members of this family are associated with human leukemias. We are interested in understanding how C/EBPε normally functions to promote neutrophil differentiation and whether therapies that promote C/EBPε activity might be used in treatment of human leukemias. Current areas of focus in this project include the evaluation of the interaction between C/EBPε and the small ubiquitin-like (SUMO) proteins and the interplay between subnuclear localization of C/EBPε and inhibition of its activity in acute promyelocytic leukemia.
- S. Sharma, E. Cobos and S.C. Williams. 2006 Posttranslational regulation of CCAAT/enhancer binding protein transcription factors. Recent Research Developments in Molecular and Cellular Biology, 6:37-64.
- Kim J, S Sharma, Y Li, E Cobos, JJ Palvimo, and SC Williams 2005 Repression and coactivation of CCAAT/enhancer binding protein epsilon by sumoylation and protein inhibitor of activated stat x proteins. J Biol Chem:280: 12246-12254.
- Nalbant, D, H Youn, I Nalbant, S Sharma, E Cobos, EG Beale, Y Du and S.C. Williams. 2005 FAM20: an evolutionarily conserved family of secreted proteins expressed in hematopoietic cells. BMC Genomics, 6:11.
- Kim, J., C.A. Cantwell, P.F. Johnson, C.M. Pfarr, and S.C. Williams. 2002. Transcriptional activity of CCAAT/enhancer binding proteins is controlled by a conserved inhibitory domain that is a target for sumoylation. J. Biol. Chem. 277:38037-38044.
2. Interkingdom signaling: hormonal interactions between pathogenic bacteria and hosts cells in burn wounds and cystic fibrosis.
The Gram negative opportunistic pathogen, Pseudomonas aeruginosa, utilizes an intercellular signaling system named quorum sensing (QS) to coordinate gene expression during infections. The P. aeruginosa QS system utilized lipid based signaling molecules (autoinducers) termed acyl homoserine lactones (AHL), which function as ligands for transcriptional regulators in P. aeruginosa. However, our focus is on the effects of one particular P. aeruginosa AHL, N-3-oxo-dodecanoyl homoserine lactone (3-O-C12-HSL) on mammalian cells in infection scenarios. 3-O-C12-HSL elicits a number of physiological effects on mammalian cells, including the induction of pro-inflammatory gene expression and the induction of apoptosis. We hypothesize that the effects of 3-O-C12-HSL are mediated through mammalian receptor proteins and are currently investigating several candidates. Other projects are looking at the kinetics of autoinducer uptake and the development of chemically-modified autoinducers whose fate can be followed in cells and living organisms. These studies may aid in the development of treatments for P. aeruginosa infections in wounds and the lungs of cystic fibrosis patients.
- Shiner, E. K., D. Terentyev, A. Bryan, S. Sennoune, R. Martinez-Zaguilan, G. Li, S. Gyorke, S. C. Williams, and K. P. Rumbaugh. 2006. Pseudomonas aeruginosa autoinducer modulates host cell responses through calcium signaling. Cell Microbiol 8:1601-10.
- Shiner, E.K., K.P. Rumbaugh and SC Williams. 2005 Interkingdom signaling: deciphering the language of acyl homoserine lactones. FEMS Microbiology Reviews, 29:935-947.
- Shiner, E.K., S. Reddy, C. Timmons, G. Li, S.C. Williams and K.P. Rumbaugh. 2004 Construction of a bacterial autoinducer detection system in mammalian cells. Biological Procedures Online, 6;268-276.
- Williams, SC, EK Patterson, NL Carty, JA Griswold, AN Hamood and KP Rumbaugh. 2004 Pseudomonas aeruginosa autoinducer enters and functions in mammalian cells. J. Bacteriology 186:2281-7.
3. Abnormal calcium handling in catecholaminergic polymorphic ventricular tacchycardia
- Terentyev, D., A. Nori, M. Santoro, S. Viatchenko-Karpinski, Z. Kubalova, I. Gyorke, R. Terentyeva, S. Vedamoorthyrao, N.A. Blom, G. Valle, C. Napolitano, S.C. Williams, P. Volpe, S.G. Priori, and S. Gyorke. 2006. Abnormal interactions of calsequestrin with the ryanodine receptor calcium release channel complex linked to exercise-induced sudden cardiac death. Circ Res 98:1151-8.
- Terentyev, D., S. Cala, T. Houle, S. Viatchenko-Karpinski, I. Gy�rke, R. Terentyeva, S.C. Williams and S. Gy�rke. 2005 Triadin overexpression stimulates excitation-contraction coupling and increases predisposition to cellular arrhythmia in cardiac myocytes. Circulation Research, 96: 651-658.
- Kubalova, Z., D. Terentyev, I. Gy�rke, S.C. Williams and S. Gy�rke. 2004 Modulation of cytosolic and intra-SR calcium waves by calsequestrin in cardiac myocytes. Journal of Physiology, 561:515-524
- Gy�rke, S., I. Gy�rke, D. Terentyev, S. Viatchenko-Karpinski, and S.C. Williams. 2004 Modulation of sarcoplasmic reticulum calcium release by calsequestrin in cardiac myocytes. Biol. Res. 37:603-607.
- Terentyev, D., S. Viatchenko-Karpinski, I. Gyorke, P. Volpe, S.C. Williams and S. Gyorke. 2003. Calsequestrin determines the functional size and stability of SR Ca stores in heart. Proc. Natl. Acad. Sci. USA. 100:11759-11764.
- Grant, C., M. Nonnemacher, P. Jain, D. Pandya, B. Irish, S.C. Williams, and B. Wigdahl. 2006. CCAAT/enhancer-binding proteins modulate human T cell leukemia virus type 1 long terminal repeat activation. Virology 348:354-369.
- Davis, R.L., A.C. Sanchez, D.J. Lindley, S.C. Williams and P.J. Syapin. Effects of mechanistically distinct NF-B inhibitors on glial inducible nitric-oxide synthase expression. Nitric Oxide: Biology and Chemistry, 12:200-209.
- Karri, S., H. Johnson, W.J. Hendry III, S.C. Williams and S.A Khan. 2004 Neonatal exposure to diethylstilbestrol leads to impaired actions of androgens in adult male hamsters. Reproductive Toxicology 19:53-63.