Interferons were first identified by their ability to confer resistance to viral infections. These hormones were later found to inhibit the proliferation of normal and tumorigenic cells, and to induce the differentiation and activation of a variety of immune cells. Clinical use of interferons has proven successful in the treatment of diseases such as hairy cell leukemia, AIDS-associated Kaposi's sarcoma, and viral hepatitis. The mechanism by which interferon functions in the control of these diseases is not known. The long range goal of the proposed project is to elucidate the molecular mechanisms of interferon action at the level of gene regulation and to understand how viral infection and oncogene expression can alter the normal regulation of interferon stimulated genes. This information should be useful in designing the implementation of interferon in the treatment of viral infections and cancer. Type I interferons induce the rapid but transient transcriptional stimulation of a particular set of genes. Interferons elicit this response by binding to specific plasma membrane receptors and subsequently transducing a signal to the transcriptional machinery in the nucleus. The genes which respond to interferon possess a cis-acting DNA sequence which is necessary for activation. Interferon-induced nuclear factors have been found to bind to this DNA element and are thereby implicated in transcriptional regulation. Adenovirus infection interferes with the normal transcriptional regulation of these interferon stimulated genes. Adenovirus has a unique and dual effect upon the expression of these genes. Infection with virus particles induces the transcription of this set of genes in the absence of interferon, whereas the adenovirus E1A oncogene suppresses their induction.
The specific aims of this proposal are to use genetic and biochemical techniques to study the transcriptional activation and repression of type I interferon stimulated genes occurring during interaction between virus and host. 1) Transcriptional repression of interferon stimulated genes by the E1A oncogene: These studies will include identification of the DNA target sequence(s) which is responsive to the action of E1A and the domain(s) of the E1A oncoprotein which is responsible for repression by employing transient co- transfection analyses with recombinant target genes and various deletions of the E1A oncogene. The ability of E1A to alter the activity of the interferon-induced transcription factors will be tested by DNA binding assays and possible protein-protein interactions. 2) Transcriptional activation of interferon stimulated genes by adenovirus infection: Analyses will be performed to identify the DNA target of adenovirus activation and induced factors which may interact with the DNA element. Comparative analyses of factors and DNA elements in the interferon system could reveal unique and/or shared signal transduction mechanisms.
| Gilmour, K C; Reich, N C (1994) Receptor to nucleus signaling by prolactin and interleukin 2 via activation of latent DNA-binding factors. Proc Natl Acad Sci U S A 91:6850-4 |
| Kotanides, H; Reich, N C (1993) Requirement of tyrosine phosphorylation for rapid activation of a DNA binding factor by IL-4. Science 262:1265-7 |
| Daly, C; Reich, N C (1993) Double-stranded RNA activates novel factors that bind to the interferon-stimulated response element. Mol Cell Biol 13:3756-64 |
| Gutch, M J; Daly, C; Reich, N C (1992) Tyrosine phosphorylation is required for activation of an alpha interferon-stimulated transcription factor. Proc Natl Acad Sci U S A 89:11411-5 |
| Gutch, M J; Reich, N C (1991) Repression of the interferon signal transduction pathway by the adenovirus E1A oncogene. Proc Natl Acad Sci U S A 88:7913-7 |
