The goal of this work is to understand how the decay rates of mRNAs are regulated in mammalian cells and how changes in mRNA half-life influence the cellular responses to growth and differentiation factors, carcinogens, and environmental stress. During the past five years, interest in mRNA stability has increased substantially, with the recognition of the links between cytoplasmic mRNA half-life and gene expression. the regulation of cytoplasmic decay rates is particularly important for mRNAs whose levels fluctuate rapidly in response to various stimuli. This proposal focuses on the regulation of two mRNAs, histone and c-myc, and on the destabilization of host mRNAs in cells infected with herpes simplex virus type 1 (HSV-1). In vitro assays plus gene transfection experiments will be used to identify the enzymes that degrade histone and c-myc mRNAs and to characterize the regulatory factors that influence their decay rates. From these two specific cases, we hope to draw some general conclusions about how the half-lives of other mRNAs are regulated. An HSV-1-encoded protein induces the destabilization of almost every host mRNA in infected cells, apparently by activating a potent mRNase activity encoded by the host. We hope to characterize the mRNase and to determine the mechanism by which it is induced. Then we can identify those factors that repress the mRNase in uninfected cells and determine the function of the mRNase.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA063676-03
Application #
2105680
Study Section
Special Emphasis Panel (SRC)
Project Start
1993-09-17
Project End
1997-06-30
Budget Start
1995-07-01
Budget End
1996-06-30
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Leeds, P; Kren, B T; Boylan, J M et al. (1997) Developmental regulation of CRD-BP, an RNA-binding protein that stabilizes c-myc mRNA in vitro. Oncogene 14:1279-86
McLaren, R S; Caruccio, N; Ross, J (1997) Human La protein: a stabilizer of histone mRNA. Mol Cell Biol 17:3028-36
Ross, J (1997) A hypothesis to explain why translation inhibitors stabilize mRNAs in mammalian cells: mRNA stability and mitosis. Bioessays 19:527-9
Ross, J (1996) Control of messenger RNA stability in higher eukaryotes. Trends Genet 12:171-5
Zelus, B D; Stewart, R S; Ross, J (1996) The virion host shutoff protein of herpes simplex virus type 1: messenger ribonucleolytic activity in vitro. J Virol 70:2411-9
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Caruccio, N; Ross, J (1994) Purification of a human polyribosome-associated 3' to 5' exoribonuclease. J Biol Chem 269:31814-21
Prokipcak, R D; Herrick, D J; Ross, J (1994) Purification and properties of a protein that binds to the C-terminal coding region of human c-myc mRNA. J Biol Chem 269:9261-9