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DEANNA S. SMITH, Ph.D.
Assistant Professor, Biological Sciences
DEGREES
Ph.D., 1994, Stanford University
RESEARCH INTERESTS
Lis1 and Cell Motility
Cells must be able to establish polarity, divide, migrate, and undergo morphological changes necessary for specific functions. Molecular motors are emerging as critical components of many of these processes, and as such are likely to be tightly regulated. Indeed, several human diseases have been linked to problems with motor proteins.
The Lis1 gene product came into the limelight in the early to mid 90's when it became apparent that loss or mutation of a single Lis1 allele causes a severe developmental brain malformation in humans, Type I Lissencephaly ( or "smooth brain"). This is characterized by reduced or absent gyri and disrupted neuronal positioning. Patients are cognitively impaired and develop increasingly severe seizures. Many children die at an early age.
Lis1 turns out to be absolutely vital for all embryonic development in mice, while heterozygotic mutations specifically disrupt brain development. It is likely that total Loss of Lis1 is also inconsistent with human development. Homologs of Lis1 exist in various organisms, including slime molds, yeasts and insects. In all systems, there is a link between Lis1 and an amazing microtubule motor, called cytoplasmic dynein.
Cytoplasmic dynein is a multisubunit machine that couples ATP hydrolysis to force generation in a microtubule-dependent fashion. It is a close relative of axonemal dyneins, which function if flagellar motility. Cytoplasmic dynein can translocate along microtubules, carrying various sorts of cargo with it, including membranous organelles and components of the cytoskelon. Motor activity has been linked to axon transport, membrane trafficking, organelle distribution, chromosome segregation, spindel orientation, and cell migration.
Another protein that may function in the Lis1 - cytoplasmic dynein pathway is Nudel, which interacts with both Lis1 and dynein. Nudel is a physiological substrate for cyclin dependent kinases, including Cdk5, which functions primaritly in the brain, and Cdc2, which functions primarily during mitosis.
The mechanisms that control dynein are just beginning to be elucidated. There is evidence for phosphorylation of dynein directly, and there is evidence that specifc subunits may confer specific functions. A multisubunit complex, dynactin, may confer cargo selectivity and could impact processivity by preventing dynein motors from diffusing away from microtubules. The interests of this laboratory are to explore the role of Lis1 and Nudel in regulating motile cell behaviors through their interactions with dynein.
There are three main projects in the lab:
- Determine if and how Lis1 and Nudel impact dynein function. Do they impact dynein's enzymatic activity, as GTPase regulatory proteins influence GTPases? Do they control dynein targeting? Dynein complexes are heterogeneous. Do Lis1 and Nudel interact with a specific subset of dynein compexes? How do cyclin dependent kinases play into Lis1 and Nudel biology? This work relies heavily on protein biochemisty, as well molecular and cell biological techniques.
- Lis1 and Nudel proteins are enriched in specific places at specific times. For example, both become very abundant in leading edges of migrating cells and in growth cones in growing axons. They accumulate the nuclear envelope at the G2/M transition, and at kinetochores during early mitosis. As kinetochores interact with microtubules, this enrichment is lost, and bth proteins seem to localize preferentially to spindle microtubules until early anaphase. Both proteins to be enriched at centrosomes. We would like to know how this targeting is accomplished and what purpose it serves. This work takes advantage of our unique antibodies and relies on state-of-the art widefield microscopy. We have several molecular tools to explore how disrupting a single protein can influence the behavior and distribution of macromolecular machines.
- The product of the adenomatous polyposis coli gene (APC) is mutated in the majority of inherited and spontaneous cases of colrectal cancer. The central hypothesis is that APC is a crucial node in a developmental pathway that is constitutively activated in colon cancer, leading to transcriptional activation of a mitotic program. Proteins that interact with APC, such as b-catenin and EB1, are of obvious interest. b-catenin expression is upregulated in cancer (as it is in development). It enters the nucleus and interacts with a family of transcription factors to regulate transcription. Recent reports have linked both proteins to cytoplasmic dynein. We are working on another aspect of this relationship, pursueing the possibility that APC and b-catenin may regulate cytoplasmic dynein. Dr. Smith is a member of the growing Center for Colon Cancer Research at USC/MUSC. This center is dedicated to the study of the biology, therapy and prevention of colon cancer.
CONTACT INFORMATION
University of South Carolina
Department of Biological Sciences, CLS 607
College of Arts and Sciences
Columbia, SC 29208
E-mail
Office: 803 . 777 . 3020 | Fax: 803 . 777 . 4002
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