Interferons (IFNs) have antiviral, cytostatic and immunomodulatory effects and have potential for use in chemotherapy both alone and in combination with other drugs. Little is known about the mechanism by which IFNs exert the cytostatic effects which serve as a basis for their use in cancer therapy. We have recently shown that IFNs alpha and beta strongly down-regulate the expression of multiple genes encoded by mitochondria in mouse and human cell-lines. This response is not a consequence of the cell-growth inhibition as it occurs rapidly and is selective. The reduction in mRNA levels is accompanied by lower rates of mitochondrial protein synthesis. This novel effect of IFNs provides a unique example of mitochondrial regulation and suggests a possible mechanism for cell-growth inhibition. We propose to investigate the mechanism by which IFNs exert this effect and its significance for cell function. In order to elucidate the molecular mechanism involved we will determine whether the reduction in mRNA levels is due to an inhibition of their synthesis or increased turnover. This information will provide the basis for future mechanistic studies. We will examine the rate of synthesis of individual proteins as well as changes in their steady-state level. The consequences of such effects on functionality of the mitochondrion will be determined by measuring specific enzyme levels, 02 consumption capability and cellular ATP levels. To test the hypothesis that impairment of mitochondrial function is partly responsible for the cytostatic responses we will seek a correlation between the dose response curves for inhibition of mitochondrial RNA and cell growth inhibition and examine cell-lines resistant to the growth inhibitory effects of IFN.
| Najarro, P; Traktman, P; Lewis, J A (2001) Vaccinia virus blocks gamma interferon signal transduction: viral VH1 phosphatase reverses Stat1 activation. J Virol 75:3185-96 |
| Lewis, J A; Huq, A; Najarro, P (1996) Inhibition of mitochondrial function by interferon. J Biol Chem 271:13184-90 |
| Lewis, J A (1995) A sensitive biological assay for interferons. J Immunol Methods 185:9-17 |
