Abstract
To identify genes that could serve as targets for novel cancer therapeutics, we used a bioinformatic analysis of microarray data comparing gene expression between normal and tumor-derived primary human tissues. From this approach, we have found that maternal embryonic leucine zipper kinase (Melk), a member of the AMP serine/threonine kinase family, exhibits multiple features consistent with the potential utility of this gene as an anticancer target. An oligonucleotide microarray analysis of multiple human tumor samples and cell lines suggests that Melk expression is frequently elevated in cancer relative to normal tissues, a pattern confirmed by quantitative reverse transcription-PCR and Western blotting of selected primary tumor samples. In situ hybridization localized Melk expression to malignant epithelial cells in 96%, 23%, and 13% of colorectal, lung, and ovarian tissue tumor samples, respectively. Expression of this gene is also elevated in spontaneous tumors derived from the ApcMin and Apc1638N murine models of intestinal tumorigenesis. To begin addressing whether Melk is relevant for tumorigenesis, RNA interference-mediated silencing within human and murine tumor cell lines was done. We show that Melk knockdown decreases proliferation and anchorage-independent growth in vitro as well as tumor growth in a xenograft model. Together, these results suggest that Melk may provide a growth advantage for neoplastic cells and, therefore, inactivation may be therapeutically beneficial.
Highlights
Progress toward effective disease management in the clinic has been achieved by an understanding of the relevant signaling pathways
We propose that maternal embryonic leucine zipper kinase
As part of an effort to identify novel drugable targets, we have found that maternal embryonic leucine zipper kinase (Melk), an AMPK-related serine/threonine kinase, is overexpressed in multiple tumor types
Summary
Progress toward effective disease management in the clinic has been achieved by an understanding of the relevant signaling pathways. Additional reported Melk substrates include ZPR9, a novel zinc finger–like protein [20], and NIPP1, a splicing factor involved in spliceosome assembly [21] Both proteins were initially discovered to associate with Melk through yeast two-hybrid screens and build on the likely involvement of Melk in the cell cycle. Vulsteke et al [21] found that the interaction between Melk and NIPP1 is largely dependent on the presence of a phosphorylated Thr478 within the COOH terminus of Melk This association between Melk and NIPP1 was maximal during mitosis and prevented spliceosome assembly in cell extracts. It is unclear whether NIPP1 is a substrate of the kinase activity of Melk, the interaction between these two proteins again supports a close link between Melk and the cell cycle
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