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Mol. Cell. Biol. 23 (7): 2251-2263

Copyright © 2003 by the American Society for Microbiology. All rights reserved.

Lysyl Oxidase Inhibits Ras-Mediated Transformation by Preventing Activation of NF-{kappa}B

Sébastien Jeay, Stefania Pianetti, Herbert M. Kagan, and Gail E. Sonenshein*

Department of Biochemistry, Boston University Medical School, Boston, Massachusetts 02118,

Received for publication 25 July 2002. Revision received 28 October 2002. Accepted for publication 3 January 2003.

Abstract: Lysyl oxidase (LO), which catalyzes the oxidation of lysine residues, was previously shown to have anti-oncogenic activity on ras-transformed cells. Since oncogenic Ras mediates transformation, in part, through the activation of the transcription factor nuclear factor-{kappa}B (NF-{kappa}B), we tested here the effects of LO on NF-{kappa}B activity. Expression of LO in ras-transformed NIH 3T3 cells led to decreased NF-{kappa}B binding and activity, as well as the expression of the NF-{kappa}B target gene c-myc. Importantly, ectopic expression of LO led to a dramatic decrease in colony formation by ras-transformed NIH 3T3 cells, a finding comparable to the expression of the I{kappa}B{alpha} dominant-negative mutant, which could be rescued by p65/p50 NF-{kappa}B subunit expression. LO was unable to directly inhibit the activity of ectopically expressed p65 and c-Rel NF-{kappa}B subunits, suggesting that LO affected an upstream signaling pathway(s) induced by Ras. Consistent with this hypothesis, LO expression decreased both the rate of I{kappa}B{alpha} turnover and the activities of IKK{alpha} and IKKß. Moreover, the ectopic expression of a constitutively active version of either kinase reversed the negative effects of LO. Ras can induce NF-{kappa}B via both the phosphatidylinositol 3-kinase (PI3K)/Akt and Raf/MEK pathways. LO potently downregulated the PI3K and Akt kinases, while partially inhibiting MEK kinase activity. Expression of a constitutively activated, myristylated Akt or PDK1 was able to counteract the effect of LO on NF-{kappa}B, whereas constitutively activated Raf was only partially effective. Importantly, LO blocked membrane localization of Akt and PDK1 in Ras-transformed cells. Overall, these results strongly argue that the anti-oncogenic effects of LO on ras-mediated transformation are due to its ability to inhibit signaling pathways that lead to activation of NF-{kappa}B.


* Corresponding author. Mailing address: Department of Biochemistry, Boston University School of Medicine, 715 Albany St., Boston MA 02118. Phone: (617) 638-4120. Fax: (617) 638-4252. E-mail: gsonensh{at}bu.edu.



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