These investigations will focus on elucidating proto-oncogene mRNA degradation in mammalian cells. The goal of these studies will be to identify the RNA structural features responsible for the liability of the growth factor-inducible c-fos proto-oncogene transcript to determine the mechanism(s) by which these instability determinants function in mRNA decay, and to characterize the cytoplasmic factors that carry out this process. The primary experimental approach to be employed will involve creating defined mutations and fusions of the c. fos gene in vitro, introducing these altered genetic constructs into mouse fitroblasts, and analyzing the decay of the resulting mRNA transcripts in vivo. Characterization of cellular mRNA degradation factors will involve tooth examining c-fos mRNA decay in cells treated with various agents that stimulate cell growth and purifying these degradation factors from cytoplasmic extracts. The results of these studies should enhance our knowledge of a fundamental aspect of gene expression that presently is poorly understood and should contribute to our long-term objective of defining the basic principles that govern mRNA decay in eukaryotic organisms. Moreover, this knowledge should ultimately be of value to understanding biological mechanisms of oncogenesis.
| Schiavi, S C; Wellington, C L; Shyu, A B et al. (1994) Multiple elements in the c-fos protein-coding region facilitate mRNA deadenylation and decay by a mechanism coupled to translation. J Biol Chem 269:3441-8 |
| Wellington, C L; Greenberg, M E; Belasco, J G (1993) The destabilizing elements in the coding region of c-fos mRNA are recognized as RNA. Mol Cell Biol 13:5034-42 |
| Schiavi, S C; Belasco, J G; Greenberg, M E (1992) Regulation of proto-oncogene mRNA stability. Biochim Biophys Acta 1114:95-106 |
| Shyu, A B; Belasco, J G; Greenberg, M E (1991) Two distinct destabilizing elements in the c-fos message trigger deadenylation as a first step in rapid mRNA decay. Genes Dev 5:221-31 |
