Simon Williams Ph.D.
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
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.