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J. Biol. Chem., Vol. 280, Issue 24, 22977-22985, June 17, 2005

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Drosophila Lysyl Oxidases Dmloxl-1 and Dmloxl-2 Are Differentially Expressed and the Active DmLOXL-1 Influences Gene Expression and Development^*

Janos Molnar, Zsuzsanna Ujfaludi, Sheri F. T. Fong, John A. Bollinger¶, Girma Waro, Ben Fogelgren, David M. Dooley¶, Matyas Mink, and Katalin Csiszar||

From the Cardiovascular Research Center, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96822, Department of Genetics and Molecular Biology, University of Szeged, Kozepfasor 52, H-6726 Szeged, Hungary, and ^¶Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana 59717

Mammalian lysyl oxidase (LOX) is essential for the catalysis of lysyl-derived cross-links in fibrillar collagens and elastin in the extracellular matrix and has also been implicated in cell motility, differentiation, and tumor cell invasion. The active LOX has been shown to translocate to the nuclei of smooth muscle cells and regulate chromatin structure and transcription. It is difficult to interpret the role of the LOX protein as it is co-expressed with other members of the LOX amine oxidase family in most mammalian cells. To investigate the function of the LOX proteins, we have characterized the Drosophila lysyl oxidases Dmloxl-1 and Dmloxl-2. We present the gene, domain structure, and expression pattern of Dmloxl-1 and Dmloxl-2 during development. In early development, only Dmloxl-1 was expressed, which allowed functional studies. We have expressed Dmloxl-1 in S2 cells and determined that it is a catalytically active enzyme, inhibited by -amino-proprionitrile (BAPN), a specific LOX inhibitor. We localized DmLOXL-1 in the nuclei in embryos and in adult salivary gland cells in the nuclei, cytoplasm, and cell surface, using immunostaining and a DmLOXL-1 antibody. To address the biological function of Dmloxl-1, we raised larvae under BAPN inhibitory conditions and over-expressed Dmloxl-1 in transgenic Drosophila. DmLOXL-1 inhibition resulted in developmental delay and a shift in sex ratio; over-expression in the w^m4 variegating strain increased drosopterin production, demonstrating euchromatinization. Our previous data on the transcriptional down-regulation of seven ribosomal genes and the glue gene under inhibitory conditions and the current results collectively support a nuclear role for Dmloxl-1 in euchromatinization and gene regulation.

Received for publication, March 18, 2005

^* This work was supported by National Institutes of Health Grants AR47713, RR03061, and GM27659. 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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) M94054, BT001394, AI260913, AC009349, AC008287, AC007803, AC007802, AJ295625, AJ295626.

^|| To whom correspondence should be addressed: 1960 East-West Rd., Honolulu, Hawaii 96822. Fax: 808-956-9481; E-mail: kcsiszar{at}aol.com.

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