Research Summary
Our research has involved the study of the insulin like growth factor type 1 receptor in malignant transformation. We have made the observation that activation of the insulin like growth factor receptor (IGF-1) is critical to the transformed phenotype in certain cell types. This observation was initially made in fibroblast cells, but has been extended to include rat and human glioblastoma cell lines, Lewis lung cancinoma cells, MCF7 breast carcinoma cells and a variety of other cancer lines.
Interference with the IGF-1 receptor and/or intracellular signals generated by the receptor inhibit anchorage independent growth and tumor formation in animals and the intracellular domain of the IGF-1 receptor that is critical to the transforming activity of the IGF-1 receptor has been identified. This critical region of the IGF-I receptor resides in the C-terminus of the receptor. It is now known that activation of the enzymes phosphoatidylinositol 3-kinase and AKT-1/PKB play a role in the transforming activity of the IGF-1 receptor via the phosphorylation of the pro-apototic BAD protein. This results in the inhibition of apoptosis which is critical to tumor formation.
We have begun to extend our studies of the role of the IGF-1 receptor in transformation into prostate cancer. This effort was prompted by the finding that high serum levels of IGF-1 in men correlates with an increased risk for prostate cancer. These results would argue that IGF-1 plays an integral role in the development of prostate cancer. In order to begin to examine this role we have chosen to utilize the microarray technique for analysis of gene expression. We have developed a cell culture system in which prostate cell lines derived from normal and malignant tissue are stimulated with individual growth factors (IGF-1, EGF). This will allow the analysis of responses to a single factor and will allow us to examine specific intracellular signals that regulate the changes in gene expression we observe.
IGF-I in Human Aging
A decline in tissue function and protein synthesis occurs with increasing age. This catabolic state is associated with a decrease in the serum levels of IGF-I and IGF-I supplementation has been proposed as a therapy for elderly individuals. Not only is there a decline in the levels of IGF-I in the serum but the response of cells to IGF-I decreases with increasing age. In vitro, human cells that have reached the end of their lifespan do not proliferate in response to IGF-I or other growth factors that will induce proliferation in the cells early in their lifespan. The reason for this lack of response is not clear and may be tied to fundamental changes within the cell that are important to the loss of function seen in "old" cells. For example, the rate of protein synthesis is regulated in part by IGF-I and, as mentioned above, protein synthesis declines with age both in the body and in vitro. An understanding of the changes in IGF-I responses are regulated and their connection to the senescent growth arrest may provide novel therapeutic approaches to some of the problems associated with aging.
Selected Publications
1. DBI-1, a novel notch related gene, is regulated by insulin like growth factor 1. (1998) H. Hoff, M. Tresini, S. Li, C. Sell Exp. Cell Res. 328: 359-370
2. A phosphatidylinositol 3-kinase inhibitor induces a senescent-like growth arrest in human diploid fibroblast cells. (1998) M. Tresini, M. Mawal-Dewan, V.J.Cristofalo, C. Sell Cancer Res.58:1-4
3. Enhanced proliferation of human fibroblasts in the presence of dexamethasone is accompanied by changes in p21Waf 1/Cip 1/Sdi 1 and the IGF-1 receptor. (1998) S. Li, Mawal-Dewn, M., V.J. Cristofalo, C.Sell J. Cell Physiol. 177:396-401
4. Activation of the insulin like growth factor type 1 receptor by deletion of amino acids 870-905. (1998) S. Li, H. Hoff, H. Zhang, C. Sell Exp. Cell Res. 243:326-333
5. The regulation of EPC1/PEDF in normal human fibroblasts is posttranscriptional. (2000) V.W. Coljee,M., Rottenberg, M. Tresini, V.J. Cristofalo, M.K. Francis, C. Sell J. Cell Biochem. 79:442-452. |
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