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Chief, Unit of Molecular Enzymology
Laboratory of Cellular and Molecular Regulation
NIMH/NIH
Bethesda, MD 20892
Adjunct Professor
Department of Biochemistry & Molecular Biology
Medical College of Virginia Campus
Virginia Commonwealth University
Richmond, VA 23298-0614
Email: milsties@mail.nih.gov
Telephone: 804-828-9330
Education
Ph.D., University of Southern California, Los Angeles, CA, 1968, Biochemistry
Post-Doc
- 1968-1972 - Senior Staff Fellow, Laboratory of Chemistry, NIAMD, NIH
- 1972-1973 - Senior Staff Fellow, Laboratory of Neurochemistry,
- National Institute of Mental Health, Bethesda, MD
- 1973-1995 - Research Chemist, Senior Investigator, Laboratory of Neurochemistry,
- National Institute of Mental Health, Bethesda, MD
Research
Research Role of Sphingolipid Metabolites in Neurobiology
Evolutionarily conserved actions of the sphingolipid metabolite,
sphingosine-1-phosphate (S1P) in yeast, plants, and mammals have shown it to
have important functions. In higher eukaryotes, S1P is the ligand for a family
of five G-protein coupled receptors. These S1P receptors are differentially
expressed, coupled to a variety of G-proteins and regulate angiogenesis,
vascular maturation, cardiac development, and immunity, and have important roles
in directed cell movement. S1P also has direct intracellular actions. Only very
recently have we begun to make progress in understanding the interplay between
the intracellular and extracellular functions of S1P. Our recent studies are
aimed at understanding these complex roles of S1P in cancer, immune responses,
and neurobiology.
Nerve growth factor (NGF), the archetypal neurotrophin, has long been recognized
for its role in survival, differentiation, axonal growth, and target innervation
of sympathetic and sensory neurons. However, the local signals that regulate
neurite extension are not well understood. A new addition to the NGF signaling
repertoire is the activation of sphingosine kinase, the enzyme that
phosphorylates sphingosine to form sphingosine-1-phosphate. We are currently
studying the role of sphingosine-1-phosphate in neuronal development and in
NGF-induced survival and elaboration of neurites. Our results raise the
intriguing possibility that abnormal sphingolipid metabolism could be involved
in the progression of neurodegenerative disorders, such as trauma, Alzheimer's,
Parkinson's, and ischemic stroke, and that known agents that interfere with or
stimulate sphingolipid metabolism might be useful therapeutic agents.
Highlights of current findings
There are two isoforms of sphingosine kinase (SphK) that catalyze the formation
of S1P. Whereas SphK1 stimulates growth and survival, we surprisingly found that
SphK2 enhanced apoptosis in diverse cell types and also suppressed cellular
proliferation. SphK2-induced apoptosis was independent of activation of S1P
receptors. Sequence analysis revealed that SphK2 contains a 9 amino acid motif
similar to that present in BH3-only proteins, a pro-apoptotic subgroup of the
Bcl-2 family. We are now examining the intriguing possibility that SphK2 is a
bona fide BH3-only protein and determining its mechanism of action.
Publications
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1101 E Marshall St | PO Box 980614 | Richmond, VA 23298 | ph 804.828.9762 | fax 804.828.1473
Site Update July 20, 2008, Responsible Unit - Department of Biochemistry & Molecular Biology, biochemgrad@mail.vcu.edu
Virginia Commonwealth University,
VCU School of Medicine
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