Anti-cancer protein transduction strategies: reconstitution of p27 tumor suppressor function.
Significant scientific effort focused on understanding the molecular basis of oncogenesis has identified multiple tumor suppressor genes and their corresponding functions. The ultimate goal of this work is to use this knowledge to devise anti-cancer strategies that specifically kill tumor cells in vivo, while leaving normal cells unharmed. Unfortunately, tumor suppressor proteins, while maintaining specificity for their intracellular targets, are often in excess of 20,000 Da and hence, undeliverable in vivo. To address the delivery problem, we previously further developed a protein transduction strategy that allows for the rapid delivery of large, biologically active proteins in excess of 100,000 Da into approximately 100% of cells in culture and most, if not all, cells/tissues in mouse models. The strategy involves the generation of an N-terminal fusion protein that contains the TAT protein transduction domain. Here the ability to manipulate tumor biology in several mouse tumor models in vivo is demonstrated by using protein transduction to delivery the p27(Kip) tumor suppressor protein. These observations serve as a starting point to further develop the delivery of peptide and proteins to specifically treat malignancies in vivo.
Snyder
Eric L
EL
Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, UCSD School of Medicine, La Jolla, CA 92093-0686, USA.
Meade
Bryan R
BR
Dowdy
Steven F
SF
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000138:chemical synthesis* / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017930:Genes, Reporter / Q000235:genetics; D015756:Genes, tat / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000138:chemical synthesis* / Q000235:genetics; D014760:Viral Fusion Proteins / Q000737:chemistry; D001616:beta-Galactosidase / Q000378:metabolism
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D014760:Viral Fusion Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D001616:beta-Galactosidase