Use of MDA-5 as an antiviral and antiproliferative agent

Abstract

The present invention relates to mda-5 nucleic acids, MDA-5 proteins, the mda-5 promoter, and related molecules, and the use of each of these elements in protecting against or limiting viral infection, controlling cell proliferation, and promoting apoptosis. It is based upon the discovery that, contrary to earlier hypotheses based on the amino acid sequence of MDA-5, the protein is not a defective ATPase but rather exhibits ATPase activity. This supports the role of MDA-5 as a RNA helicase protein and consequently its use in promoting RNA degradation, for example in the context of antiviral defense, limitation of cell proliferation, or induction of apoptosis.

Description

SPECIFICATION[0001] This application is a continuation-in-part of International Patent Application No. PCT / US01 / 06960, filed Feb. 28, 2001 and published in English on Sep. 7, 2001 as Publication No. WO 01 / 64707, which is a continuation-in-part of U.S. patent application Ser. No. 09 / 515,363, filed Feb. 29, 2000.1. INTRODUCTION[0003] The present invention relates to melanoma differentiation associated gene-5 (mda-5) nucleic acids, MDA-5 proteins, and the mda-5 gene promoter and related molecules, and the use of these elements to protect against or limit viral infection, to control cell proliferation and to induce apoptotic cell death. It is based, at least in part, on the discovery that MDA-5 protein exhibits ATPase activity.2. BACKGROUND OF THE INVENTION2.1 Differentiation Therapy[0004] Terminal differentiation is essential for normal development and homeostasis (Leszczyniecka et al., 2001, Pharmacol Ther 90(2-3):105-56). However, this process can go awry in cancer cells, resulting i...

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However, this process can go awry in cancer cells, resulting in uncontrolled proliferation and an inability to respond to normal growth-inhibitory signals (Fisher et al., 1985, Pharmacol Ther 27(2):143-66; Waxman S., 1995, Differentiation Therapy, Waxman, ed., Sereno Symposium Publications: Rome, Italy. pp.

Moreover, as cancer cells evolve, ultimately developing new phenotypes or acquiring a further elaboration of pre-existing transformation-related properties, the expression of differentiation-associated traits often undergoes a further decline.

PCT / US01 / 06960 suggests that because of this sequence divergence, MDA-5 may not bind ATP effectively, and therefore may be an ATPase defective helicase, or may require a different energy source and / or metals for activity.

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