The long-term objective of this application is an understanding of the mechanism of action of interferons (IFNs) and tumor necrosis factor (TNF). IFNs are currently being evaluated as anticancer agents in clinical trials, wheras TNF is being considered for such use, but we do not yet understand the mechanism of action of these agents. IFNs bind to receptors on the plasmamembrane and the IFN/receptor complexes communicate signals which induce transcription of a set of genes and synthesis of several proteins. It is not known whether some of these proteins have antiproliferative activity. Studies on TNF will initially establish whether it binds to specific receptors on the plasmamembrane of sensitive cells. TNF has been labeled to high specific activity without loss of biological activity and its interaction with cells in culture will be studied by the same approach employed to characterize IFN receptors. Subsequent studies will investigate the mechanism of action of TNF, which is basically different from that of IFNs, since RNA synthesis is not required for the cytostatic or cytolytic activity of TNF. Experiments are proposed to examine whether protein synthesis is required for these effects of TNF. Other studies will investigate the synergism of action between TNF and IFNs to test a working hypothesis that IFNs induce synthesis of TNF receptors and augment in this way the cytotoxic response to TNF. Studies on the antiproliferative effect of IFNs will pursue two separate lines of research. Elevated levels of 5'-methylthioadenosine (MTA) have been detected in IFN-treated cells sensitive to growth inhibition by IFN, but not in resistant cells. MTA is formed from S-adenosylmethione (AdoMet) and it is an intermediate in the biosynthesis of polyamines. MTA is toxic for cells in culture and it seams possible that its accumulation in IFN-treated cells may contribute to growth inhibition. The cause for MTA accumulation will be examined by measuring enzymatic activities involved in MTA and AdoMet metabolism. Another line of research will examine the antiproliferative effects of IFNs on human osteosarcoma cells which are highly sensitive to growth inhibition. The synthesis of sis mRNA and the secretion of PDGF will be measured in cells adapted to growth in serum-free medium, which synthesize elevated levels of PDGF and may be dependent on autocrine stimulation for cell growth. The effect of IFNs on PDGF receptors will also be evaluated by binding assays with labeled PDGF.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA029895-09
Application #
3168918
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1981-05-01
Project End
1992-04-30
Budget Start
1990-05-01
Budget End
1992-04-30
Support Year
9
Fiscal Year
1990
Total Cost
Indirect Cost
Name
State University of New York at Albany
Department
Type
Schools of Arts and Sciences
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12222
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Gorospe, M; Kumar, S; Baglioni, C (1993) Tumor necrosis factor increases stability of interleukin-1 mRNA by activating protein kinase C. J Biol Chem 268:6214-20
Melendez, J A; Baglioni, C (1993) Differential induction and decay of manganese superoxide dismutase mRNAs. Free Radic Biol Med 14:601-8
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Diemer, V; Hoyle, M; Baglioni, C et al. (1992) Expression of porcine complement cytolysis inhibitor mRNA in cultured aortic smooth muscle cells. Changes during differentiation in vitro. J Biol Chem 267:5257-64
Melendez, J A; Baglioni, C (1992) Reduced expression of manganese superoxide dismutase in cells resistant to cytolysis by tumor necrosis factor. Free Radic Biol Med 12:151-9
Kumar, S; Millis, A J; Baglioni, C (1992) Expression of interleukin 1-inducible genes and production of interleukin 1 by aging human fibroblasts. Proc Natl Acad Sci U S A 89:4683-7
Millis, A J; McCue, H M; Kumar, S et al. (1992) Metalloproteinase and TIMP-1 gene expression during replicative senescence. Exp Gerontol 27:425-8
Peppel, K; Baglioni, C (1991) Deadenylation and turnover of interferon-beta mRNA. J Biol Chem 266:6663-6
Kumar, S; Baglioni, C (1991) Protection from tumor necrosis factor-mediated cytolysis by overexpression of plasminogen activator inhibitor type-2. J Biol Chem 266:20960-4

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