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J. Biol. Chem., Vol. 279, Issue 39, 40593-40600, September 24, 2004

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The Propeptide Domain of Lysyl Oxidase Induces Phenotypic Reversion of Ras-transformed Cells^*

Amitha H. Palamakumbura, Sébastien Jeay, Ying Guo, Nicole Pischon, Pascal Sommer¶, Gail E. Sonenshein, and Philip C. Trackman||

From the Division of Oral Biology, Boston University Goldman School of Dental Medicine and Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118 and the ^¶Institut de Biologie et Chimie des Protéines, CNRS UMR 5086, Université Claude Bernard, 69367 Lyon Cedex 07, France

Lysyl oxidase is an extracellular enzyme critical for the normal biosynthesis of collagens and elastin. In addition, lysyl oxidase reverts ras-mediated transformation, and lysyl oxidase expression is down-regulated in human cancers. Since suramin inhibits growth factor signaling pathways and induces lysyl oxidase in ras-transformed NIH3T3 cells (RS485 cells), we sought to investigate the effects of suramin on the phenotype of transformed cells and the role of lysyl oxidase in mediating these effects. Suramin treatment resulted in a more normal phenotype as judged by growth rate, cell cycle parameters, and morphology. -aminopropionitrile, the selective inhibitor of lysyl oxidase enzyme activity, was remarkably unable to block suramin-induced reversion. By contrast, ectopic antisense lysyl oxidase demonstrated that lysyl oxidase gene expression mediated phenotypic reversion. Since lysyl oxidase is synthesized as a 50 kDa precursor and processed to a 30 kDa active enzyme and 18 kDa propeptide, the effects of these two products on the transformed phenotype of RS485 cells were then directly assessed in the absence of suramin. Here we report, for the first time, that the lysyl oxidase propeptide, and not the lysyl oxidase enzyme, inhibits ras-dependent transformation as determined by effects on cell proliferation assays, growth in soft agar, and Akt-dependent induction of NF-B activity. Thus, the lysyl oxidase propeptide, which is released during extracellular proteolytic processing of pro-lysyl oxidase, functions to inhibit ras-dependent cell transformation.

Received for publication, June 14, 2004 , and in revised form, July 9, 2004.

^* This work was supported by Grants DE12425 and DE12209 (to P. C. T.) and ES11624 and CA82742 (to G. E. S.) from the National Institutes of Health, Grant DAMD170310452 (to S. J.) from the Department of the Army, and by a fellowship from the Deutsche Forschungsgemeinschaft (Germany) (to N. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Division of Oral Biology, Boston University Goldman School of Dental Medicine, 700 Albany St., Room W-210, Boston, MA 02118-2394. Tel.: 617-638-4076; E-mail: trackman{at}bu.edu.

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