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J Biol Chem, Vol. 273, Issue 25, 15313-15316, June 19, 1998

COMMUNICATION
Agmatine Suppresses Proliferation by Frameshift Induction of Antizyme and Attenuation of Cellular Polyamine Levels

Joseph Satriano^§, Senya Matsufuji, Yasuko Murakami, Mark J. Lortie, Doron Schwartz, Carolyn J. Kelly, Shin-ichi Hayashi, and Roland C. Blantz^§

From the  Division of Nephrology-Hypertension and the ^§ Program in Molecular Pathology, Department of Medicine, University of California San Diego and Veterans Affairs Medical Center, La Jolla, California 92161, and the  Jikei University School of Medicine, Department of Biochemistry II, Minato-ku, Tokyo 105, Japan

Polyamines are required for entry and progression of the cell cycle. As such, augmentation of polyamine levels is essential for cellular transformation. Polyamines are autoregulated through induction of antizyme, which represses both the rate-limiting polyamine biosynthetic enzyme ornithine decarboxylase and cellular polyamine transport. In the present study we demonstrate that agmatine, a metabolite of arginine via arginine decarboxylase (an arginine pathway distinct from that of the classical polyamines), also serves the dual regulatory functions of suppressing polyamine biosynthesis and cellular polyamine uptake through induction of antizyme. The capacity of agmatine to induce antizyme is demonstrated by: (a) an agmatine-dependent translational frameshift of antizyme mRNA to produce a full-length protein and (b) suppression of agmatine-dependent inhibitory activity by either anti-antizyme IgG or antizyme inhibitor. Furthermore, agmatine administration depletes intracellular polyamine levels to suppress cellular proliferation in a transformed cell line. This suppression is reversible with polyamine supplementation. We propose a novel regulatory pathway in which agmatine acts as an antiproliferative molecule and potential tumor suppressor by restricting the cellular polyamine supply required to support growth.

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Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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