Adhesive interactions between a cell and its neighbors, or between cells and the extracellular matrix, play a major role in the regulation of normal cellular growth and differentiation. Conversely, aberrations in cell interactions are a hallmark characteristic of the invasive and metastatic behavior of malignant cells. Research in this laboratory centers on the biology, biochemistry and molecular biology of the integrin family of membrane receptors which mediate cell-matrix interactions. We have shown that integrins regulate key signaling pathways, particularly those involving mitogen activated protein kinases (MAP kinases). Ultimately, integrin mediated signals help to control gene expression and can influence cell differentiation, traverse through the cell cycle, or apoptosis. Part of our work has focused on identifying proteins that interact with integrins, using two-hybrid screens or other approaches. We have recently analyzed a novel cytosolic protein, termed Nischarin, that binds the a5b1 integrin, and that regulates cell migration by inhibiting PAK-family kinases. Nischarin is highly expressed in the central nervous system and may play a particularly important role in regulating axon extension.
Macromolecular Therapeutics
Perhaps the most fundamental approach to the control of cancer would be to be able to regulate the aberrant expression of key genes involved in cancer progression. We have adopted two strategies in pursuit of this goal. In one strategy we use antisense oligonucleotides or RNA interference to inhibit messenger RNA from cancer-related genes. In another approach we have sought to identify novel peptides that can interact directly with the DNA of cancer-related genes. Thus we make use of a so-called "combinatorial library" strategy to select active DNA-binding peptides from a vast number of possibilities, and then couple these peptides to transcriptional regulatory domains to form novel, specific transcription factors. This is an exciting approach that could give rise to new insights into protein-DNA interactions as well as yielding new therapeutic entities.
Recent Publications:
Fisher, M., Abramov, M., Van Aerschot, A., Xu, D., Juliano, R.L., Herdewijn, P. Inhibition of MDR1 expression with altritol-modified siRNAs. Nuc Acid Res. 2007 [epub]. Abstract
Reddig, P.J., Xu, D., and Juliano, R.L.. (2005) Regulation of p21-activated kinase-independent Rac1 signal transduction by
Nischarin. J Biol Chem 280(35): 30994-1002. Abstract
Juliano, R.L., and Edin, M.L. (2005) Raf-1 serine 338 phosphorylation plays a key role in adhesion-dependent
activation of extracellular signal-regulated kinase by epidermal growth
factor. Mol Cell Biol 25(11): 4466-75. Abstract
Chaltin, P., Margineanu, A., Marchand, D., Van Aerschot, A., Rozenski, J., De Schryver, F., Herrmann, A., Mullen, K.,
Juliano, R., Fisher, M.H., Kang, H., De Feyter, S., and Herdewijn, P. (2005) Delivery of antisense oligonucleotides using
cholesterol-modified sense dendrimers and cationic lipids. Bioconjug Chem 16(4): 827-36. Abstract
Xu, D., McCarty, D., Fernandes, A., Fisher, M., Samulski, R.J., and Juliano, R.L. (2005) Delivery of MDR1 small Interfering RNA
by self-complementary recombinant adeno-associated virus vector. Mol Ther 11(4): 523-30. Abstract
Juliano, R.L., Dixit, V.R., Kang, H., Kim, T.Y., Miyamoto, Y., and Xu, D. (2005) Epigenetic manipulation of gene
expression: a toolkit for cell biologists. J Cell Biol 169(6): 847-857. Abstract
