Professor, Cellular & Molecular Medicine; Investigator, Howard Hughes Medical Institute; Molecular Cell Biology Track Leader; Cancer Biology Focus Leader
Ph.D., University of California, Irvine
Regulation of G1 Cell Cycle Progression in Cancer - Cell cycle progression from early G1 to late G1 and then into S phase requires both increased cellular growth, resulting in an accumulation of mass, and the concerted activities of multiple cyclin-dependent kinases (cdk), cdk inhibitors and tumor suppressors. The vast majority of malignant cells selectively target these pathways for alteration. Our lab is focused on determining the consequences of these genetic and epigenetic alterations and the mechanism that cell growth activates the cell cycle machinery. Recent work has shown that Rb is activated by mono-phosphorylation via cyclin D:cdk4/6 complexes and that cyclin E:Cdk2 complexes perform the inactivating hyper-phosphorylation of Rb at the Restriction Point. How cyclin E:Cdk2 becomes activated remains a mystery and is an extremely important question for understanding carcinogenesis as all tumors deregulate Restriction point control.
We are also interested in developing novel macromolecular delivery of siRNAs to induce synthetic lethal RNAi responses to treat cancer macromolecular therapeutics. Delivery across the cell membrane is generally restricted to small molecules less than 500 Daltons in size. However, peptides, proteins, siRNAs are in vast excess to this bioavailability limitation. Consequently, we have focused a lot of our attention on delivery by protein transduction domains (PTDs)/cell penetrating peptides (CPPs), such as the TAT peptide. Our recent work has uncovered the mechanism that these peptides enter cells, namely macropinocytosis, a specialized form of fluid phase endocytosis, and devised methods to enhance endosomal escape. In addition, we have a nucleic acid chemistry group in my lab that has synthesized an entirely new class of siRNAs that we are beginning to test biologically in vitro and in vivo in metastatic models of ovarian cancer.
BMS Focus Areas:
Eguchi, A., Meade, B.R., Fredrickson, C.T., Willert, K., Puri, N. & Dowdy, S.F. Efficient siRNA Delivery into Primary Cells by Peptide Transduction-dsRNA Binding Domain (PTD-DRBD) Fusion Protein. Nature Biotechnology 27:567-571 (2009).
Michiue, H., Eguchi, A., Meade, B.R., Scadeng, M. & Dowdy, S.F. Induction of In Vivo Synthetic Lethal RNAi Responses to Treat Glioblastoma. Cancer Biology & Therapeutics 8:2306-2313 (2009).
Meade, B.R. & Dowdy, S.F. The Road to Therapeutic RNA Interference (RNAi): Tackling the 800 Pound siRNA Delivery Gorilla. Discovery Medicine. 8:253-256 (2009).
Gump, J.M., June, R. & Dowdy, S.F. Revised Role of Glycosaminoglycans in TAT PTD-Mediated Cellular Transduction. Journal of Biological Chemistry 285:1500-1507 (2010).
Narashima, A. Shi, W. & Dowdy, S.F. Cell Cycle Controls in G1 and G0. Encyclopedia of Biological Chemistry (in press)(2010).
June, R.K., Gogoi, K., Eguchi, A., Cui, X.-S. & Dowdy, S.F. Synthesis of a pH-Sensitive Nitrilotriacetic Linker to Peptide Transduction Domains to Enable Intracellular Delivery of Histidine Imidazole Ring-Containing Macromolecules. Journal of the American Chemical Society (JACS) (in press)(2010).
Shapiro, G.S., Narasimha, A.M. & Dowdy, S.F. Mono-Phosphorylated Rb Activated by Cyclin D:Cdk4/6 Complexes Regulates the DNA Damage Response. (submitted).