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Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells

Authors

  • Ichiro Nakano,

    1. Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California
    2. Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California
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  • Michael Masterman-Smith,

    1. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California
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    • M.M.-S. and K.S. contributed equally to this work.

  • Kuniyasu Saigusa,

    1. Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California
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    • M.M.-S. and K.S. contributed equally to this work.

  • Andres A. Paucar,

    1. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California
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  • Steve Horvath,

    1. Department of Biostatistics, School of Public Health, UCLA, Los Angeles, California
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  • Lorelei Shoemaker,

    1. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California
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  • Momoko Watanabe,

    1. Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California
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  • Alejandra Negro,

    1. The Burnham Institute, La Jolla, California
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  • Ruchi Bajpai,

    1. The Burnham Institute, La Jolla, California
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  • Amy Howes,

    1. The Burnham Institute, La Jolla, California
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  • Vincent Lelievre,

    1. Department of Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, California
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  • James A. Waschek,

    1. Department of Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, California
    2. The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California
    3. The Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, California
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  • Jorge A. Lazareff,

    1. Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California
    2. The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California
    3. Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California
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  • William A. Freije,

    1. Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, California
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  • Linda M. Liau,

    1. Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, California
    2. The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California
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  • Richard J. Gilbertson,

    1. Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee
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  • Timothy F. Cloughesy,

    1. The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California
    2. Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California
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  • Daniel H. Geschwind,

    1. Department of Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, California
    2. The Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, California
    3. Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California
    4. Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California
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  • Stanley F. Nelson,

    1. The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California
    2. Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California
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  • Paul S. Mischel,

    1. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California
    2. The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California
    3. Department of Pathology, David Geffen School of Medicine at UCLA, Los Angeles, California
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  • Alexey V. Terskikh,

    1. The Burnham Institute, La Jolla, California
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  • Harley I. Kornblum

    Corresponding author
    1. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California
    2. Department of Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, California
    3. The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California
    4. The Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA, Los Angeles, California
    5. Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California
    • Room 1126 CIMI, 700 Westwood Plaza, Los Angeles, CA 90095
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Abstract

Emerging evidence suggests that neural stem cells and brain tumors regulate their proliferation via similar pathways. In a previous study, we demonstrated that maternal embryonic leucine zipper kinase (Melk) is highly expressed in murine neural stem cells and regulates their proliferation. Here we describe how MELK expression is correlated with pathologic grade of brain tumors, and its expression levels are significantly correlated with shorter survival, particularly in younger glioblastoma patients. In normal human astrocytes, MELK is only faintly expressed, and MELK knockdown does not significantly influence their growth, whereas Ras and Akt overexpressing astrocytes have up-regulated MELK expression, and the effect of MELK knockdown is more prominent in these transformed astrocytes. In primary cultures from human glioblastoma and medulloblastoma, MELK knockdown by siRNA results in inhibition of the proliferation and survival of these tumors. Furthermore, we show that MELK siRNA dramatically inhibits proliferation and, to some extent, survival of stem cells isolated from glioblastoma in vitro. These results demonstrate a critical role for MELK in the proliferation of brain tumors, including their stem cells, and suggest that MELK may be a compelling molecular target for treatment of high-grade brain tumors. © 2007 Wiley-Liss, Inc.

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