{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:43:43Z","timestamp":1791297823896,"version":"4.1.0"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2007,2,6]],"date-time":"2007-02-06T00:00:00Z","timestamp":1170720000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"},{"start":{"date-parts":[[2007,2,6]],"date-time":"2007-02-06T00:00:00Z","timestamp":1170720000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Breast Cancer Res"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                        <jats:title>Introduction<\/jats:title>\n                        <jats:p>Cancer therapies directed at specific molecular targets in signaling pathways of cancer cells, such as tamoxifen, aromatase inhibitors and trastuzumab, have proven useful for treatment of advanced breast cancers. However, increased risk of endometrial cancer with long-term tamoxifen administration and of bone fracture due to osteoporosis in postmenopausal women undergoing aromatase inhibitor therapy are recognized side effects. These side effects as well as drug resistance make it necessary to search for novel molecular targets for drugs on the basis of well-characterized mechanisms of action.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>Using accurate genome-wide expression profiles of breast cancers, we found <jats:italic>maternal embryonic leucine-zipper kinase<\/jats:italic> (<jats:italic>MELK<\/jats:italic>) to be significantly overexpressed in the great majority of breast cancer cells. To assess whether <jats:italic>MELK<\/jats:italic> has a role in mammary carcinogenesis, we knocked down the expression of endogenous <jats:italic>MELK<\/jats:italic> in breast cancer cell lines using mammalian vector-based RNA interference. Furthermore, we identified a long isoform of Bcl-G (Bcl-G<jats:sub>L<\/jats:sub>), a pro-apoptotic member of the Bcl-2 family, as a possible substrate for MELK by pull-down assay with recombinant wild-type and kinase-dead MELK. Finally, we performed TUNEL assays and FACS analysis, measuring proportions of apoptotic cells, to investigate whether MELK is involved in the apoptosis cascade through the Bcl-G<jats:sub>L<\/jats:sub>-related pathway.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>Northern blot analyses on multiple human tissues and cancer cell lines demonstrated that <jats:italic>MELK<\/jats:italic> was overexpressed at a significantly high level in a great majority of breast cancers and cell lines, but was not expressed in normal vital organs (heart, liver, lung and kidney). Suppression of <jats:italic>MELK<\/jats:italic> expression by small interfering RNA significantly inhibited growth of human breast cancer cells. We also found that MELK physically interacted with Bcl-G<jats:sub>L<\/jats:sub> through its amino-terminal region. Immunocomplex kinase assay showed that Bcl-G<jats:sub>L<\/jats:sub> was specifically phosphorylated by MELK <jats:italic>in vitro<\/jats:italic>. TUNEL assays and FACS analysis revealed that overexpression of wild-type MELK suppressed Bcl-G<jats:sub>L<\/jats:sub>-induced apoptosis, while that of D150A-MELK did not.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusion<\/jats:title>\n                        <jats:p>Our findings suggest that the kinase activity of MELK is likely to affect mammary carcinogenesis through inhibition of the pro-apoptotic function of Bcl-G<jats:sub>L<\/jats:sub>. The kinase activity of MELK could be a promising molecular target for development of therapy for patients with breast cancers.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/bcr1650","type":"journal-article","created":{"date-parts":[[2007,2,6]],"date-time":"2007-02-06T10:24:41Z","timestamp":1170757481000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":158,"title":["Involvement of maternal embryonic leucine zipper kinase (MELK) in mammary carcinogenesis through interaction with Bcl-G, a pro-apoptotic member of the Bcl-2 family"],"prefix":"10.1186","volume":"9","author":[{"given":"Meng-Lay","family":"Lin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Hyun","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiko","family":"Nishidate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toyomasa","family":"Katagiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2007,2,6]]},"reference":[{"key":"1615_CR1","doi-asserted-by":"publisher","first-page":"1727","DOI":"10.1016\/S0140-6736(05)66546-4","volume":"365","author":"U Veronesi","year":"2005","unstructured":"Veronesi U, Boyle P, Goldhirsch A, Orecchia R, Viale G: Breast cancer. 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