Human interferon-alpha and -Beta (Hu-IFN-alpha, Hu-IFN-Beta) were among the first cytokines purified, cloned and introduced into the clinical arena. These interferons are in use for worldwide for use in treating various cancers, viral diseases, multiple sclerosis and other diseases. Knowledge of the receptor which binds these interferons and its signal transduction mechanisms are directly relevant to understanding the activities of the interferons. This proposal describes a procedure to isolate and identify all the constituents of the human Type I interferon (Hu-IFN-alpha/Beta) receptor. By a new technology, a yeast artificial chromosome (YAC) was isolated (alphaYAC) that expresses activity of a functional Type I human interferon receptor.
The specific aims of this project are: to characterize the responses of the functional receptor to the Type I interferons; to determine the genes necessary for Type I interferon receptor function; to isolate the cDNA clones responsible for Type I IFN receptor activity; to reconstitute the receptor complex in heterologous cells (mouse and/or hamster cells); to carry out a structure/activity analysis of the receptor components by site-specific mutagenesis; to complement cells with mutations in the Type I interferon receptor and signal transduction pathways with the alphaYAC and cDNA clones; and to determine the expression of the various functional cDNA components in normal tissues and tumors. The alphaYAC clone provides the basis for these studies. Homologous recombination in yeast cells containing the alphaYAC will allow us to define the relevant genes responsible for Type I receptor function. It will be possible to reconstitute Type I human interferon receptor function by transfection of these cDNA expression vectors into heterologous cells (hamster and mouse cells); to delineate the various signal transduction mechanisms for the Type I interferons; and to evaluate their expression in normal and tumor tissues. Identification of all the components of the Type I interferon receptor will provide an understanding of the ligand-receptor interactions, the details of the signal transduction mechanisms and provide us with an opportunity to develop second generation interferons that exhibit fewer side effects and have improved efficacy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI036450-05
Application #
2886936
Study Section
Virology Study Section (VR)
Program Officer
Ridge, John P
Project Start
1995-09-30
Project End
2000-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Genetics
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Krause, Christopher D; Izotova, Lara S; Pestka, Sidney (2013) Analytical use of multi-protein Fluorescence Resonance Energy Transfer to demonstrate membrane-facilitated interactions within cytokine receptor complexes. Cytokine 64:298-309
Krause, Christopher D; Digioia, Gina; Izotova, Lara S et al. (2013) Improving the spectral analysis of Fluorescence Resonance Energy Transfer in live cells: application to interferon receptors and Janus kinases. Cytokine 64:272-85
Krause, Christopher D; Digioia, Gina; Izotova, Lara S et al. (2013) Ligand-independent interaction of the type I interferon receptor complex is necessary to observe its biological activity. Cytokine 64:286-97
Walberg, Kristin; Baron, Samuel; Poast, Joyce et al. (2008) Interferon protects mice against inhalation anthrax. J Interferon Cytokine Res 28:597-601
Krause, Christopher D; Pestka, Sidney (2007) Historical developments in the research of interferon receptors. Cytokine Growth Factor Rev 18:473-82
Qu, Yongxia; Adler, Victor; Izotova, Lara et al. (2007) The dual-specificity kinases, TOPK and DYRK1A, are critical for oocyte maturation induced by wild-type--but not by oncogenic--ras-p21 protein. Front Biosci 12:5089-97
Krause, Christopher D; Yang, Zhi-Hong; Kim, Young-Sun et al. (2007) Protein arginine methyltransferases: evolution and assessment of their pharmacological and therapeutic potential. Pharmacol Ther 113:50-87
Pestka, Sidney (2007) The interferons: 50 years after their discovery, there is much more to learn. J Biol Chem 282:20047-51
Krause, Christopher D; Mei, Erwen; Mirochnitchenko, Olga et al. (2006) Interactions among the components of the interleukin-10 receptor complex. Biochem Biophys Res Commun 340:377-85
Qu, Yongxia; Adler, Victor; Chu, Tearina et al. (2006) Two dual specificity kinases are preferentially induced by wild-type rather than by oncogenic RAS-P21 in Xenopus oocytes. Front Biosci 11:2420-7

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