Eileen Adamson's Research Focus
Genes are the controllers of our living cells that determine our individual characteristics, good and bad! Many genes can become deregulated in cancer, also in an individually specific way. Those genes have to be detected from among the 35,000 or so genes that we have. Dr. Adamson’s laboratory worked on a new way to find out which genes are deregulated using a method that scans thousands of genes at a time in a novel modification of a process called "high throughput microarray analysis." Their method was designed to detect the regulatory parts of active genes that are deregulated by a single key regulatory protein facto. The usual microarray assay used by others detects all the active normal genes as well as the abnormal genes, followed by a complex mathematical analysis to make sense of the results. The new procedure developed by the Adamson laboratory was used first to detect the genes that are abnormally active in prostate cancer. The aim was to test the active gene profile of the prostate cancer cells in each patient to make an individual analysis. To do this they are making a microarray that represents all the human genes, derived from the “regulatory domains of genes” and this is the novel aspect of our method. Dr. Adamson and her colleagues wrote a review in the journal Tumor Biology, which lists of some of the genes that are abnormally active in prostate cancer. This is only a small fraction of the genes that her group is collecting for this analysis. They collaborated with many colleagues in order to make the correct portion of these genes to put on the array. Dr. Adamson believed that this kind of analysis has many advantages and is an effective and simpler way to find out which genes are deregulated, helping the clinician to make better decisions on treatment and eventually lead to a specific gene-directed therapy.
Eileen Adamson's Research Report
Molecular Studies of Murine Development and Cancer
Roles of the Transcription Factor, Egr-1
Egr-1 transcription factor regulates genes that contribute to transformed (tumorigenic) growth. Some tumor cells and tissues express little or no Egr-1, in contrast to their normal counterparts, and as a result, proliferate faster. At least one target of regulation by Egr-1 is the gene coding for Transforming Growth Factor beta, a growth inhibitor for certain types of cells. The Figure shows a cartoon of some of the genes regulated by Egr-1. A second role for Egr-1 is the promotion of cell survival after stress such as ultraviolet irradiation of cells. Cells over-expressing Egr-1 survive stress by reduction of apoptosis (programmed cell death) by the regulation of a number of unidentified genes. This year, we have devised a new method for isolating and cloning the genes that Egr-1 regulates. The characterization of these genes will allow us to follow the signaling pathways that lead to specific cell reponses after the Egr-1 gene is induced by extracellular stimuli. Eventually, we may identify most of the genes that act downstream of Egr-1 during its many functions in the regulation of cell responses.
Growth Factors and Their Receptors in Early Development
Receptors for epidermal growth factor (EGF) transmit a signal into the cell after the binding of extracellular EGF or related ligands such as TGF-alpha and Amphiregulin (Ar) The preimplantation mouse embryo expresses both the receptor and Ar, which together play roles stimulating growth and development . Cripto (Cr-1), is an EGF-related growth factor that when inactivated, inhibits mammary cell growth and causes the lethality of embryos. We showed that inactivation of the Cr-1 gene in mouse embryos leads to developmental defects and prevents heart cell differentiation. Both the Cr-1 and EGF receptor genes are required for development and both are often over-expressed in tumors. Animal models that over-express these genes are being made to test if this leads to tumorigenesis and toward finding new ways of intervening with unregulated growth.
Role of Vinculin in Development, Cell Adhesion and Cell Motility
The roles of vinculin (a cytoskeletal protein) were studied by ablating both genes in F9 embryonal carcinoma (EC) cells, ES cells and in the mouse. We have "knocked out" the vinculin gene in cells and animals. The loss of all vinculin expression in embryos is lethal in midgestation. Vinculin null embryo cells adhere poorly to matrix, move faster, have a more rounded shape, and at least in culture proliferate faster than normal cells. These defects explain in part why development ceases at this early stage. Reduced expression of vinculin is often found in tumor cells, and this is accompanied by poor cell adhesion and increased mobility, suggesting that loss of vinculin expression may contribute to the metastatic behavior of tumor cells.
Eileen Adamson's Bio
Eileen D. Adamson earned her Ph.D. in biochemistry from the University of Toronto in 1970 followed by postdoctoral training in embryology at the University of Oxford, UK. Dr. Adamson was recruited to Sanford-Burnham Medical Research Institute in 1980 and retired in 2010.