Document Detail


Tumor-specific activation of the C-JUN/MELK pathway regulates glioma stem cell growth in a p53-dependent manner.
MedLine Citation:
PMID:  23339114     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Accumulated evidence suggests that glioma stem cells (GSCs) may contribute to therapy resistance in high-grade glioma (HGG). Although recent studies have shown that the serine/threonine kinase maternal embryonic leucine-zipper kinase (MELK) is abundantly expressed in various cancers, the function and mechanism of MELK remain elusive. Here, we demonstrate that MELK depletion by shRNA diminishes the growth of GSC-derived mouse intracranial tumors in vivo, induces glial fibrillary acidic protein (+) glial differentiation of GSCs leading to decreased malignancy of the resulting tumors, and prolongs survival periods of tumor-bearing mice. Tissue microarray analysis with 91 HGG tumors demonstrates that the proportion of MELK (+) cells is a statistically significant indicator of postsurgical survival periods. Mechanistically, MELK is regulated by the c-Jun NH(2)-terminal kinase (JNK) signaling and forms a complex with the oncoprotein c-JUN in GSCs but not in normal progenitors. MELK silencing induces p53 expression, whereas p53 inhibition induces MELK expression, indicating that MELK and p53 expression are mutually exclusive. Additionally, MELK silencing-mediated GSC apoptosis is partially rescued by both pharmacological p53 inhibition and p53 gene silencing, indicating that MELK action in GSCs is p53 dependent. Furthermore, irradiation of GSCs markedly elevates MELK mRNA and protein expression both in vitro and in vivo. Clinically, recurrent HGG tumors following the failure of radiation and chemotherapy exhibit a statistically significant elevation of MELK protein compared with untreated newly diagnosed HGG tumors. Together, our data indicate that GSCs, but not normal cells, depend on JNK-driven MELK/c-JUN signaling to regulate their survival, maintain GSCs in an immature state, and facilitate tumor radioresistance in a p53-dependent manner.
Authors:
Chunyu Gu; Yeshavanth K Banasavadi-Siddegowda; Kaushal Joshi; Yuko Nakamura; Habibe Kurt; Snehalata Gupta; Ichiro Nakano
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Stem cells (Dayton, Ohio)     Volume:  31     ISSN:  1549-4918     ISO Abbreviation:  Stem Cells     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-25     Completed Date:  2014-05-02     Revised Date:  2014-08-17    
Medline Journal Info:
Nlm Unique ID:  9304532     Medline TA:  Stem Cells     Country:  United States    
Other Details:
Languages:  eng     Pagination:  870-81     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 AlphaMed Press.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / physiology
Brain Neoplasms / genetics,  metabolism*,  pathology*
Cell Growth Processes / physiology
Female
Gene Knockdown Techniques
Glioma / genetics,  metabolism,  pathology*
Heterografts
Humans
Mice
Mice, Nude
Neoplastic Stem Cells / metabolism,  pathology*
Protein-Serine-Threonine Kinases / biosynthesis,  genetics,  metabolism*
Proto-Oncogene Proteins c-jun / genetics,  metabolism*
Signal Transduction
Tumor Suppressor Protein p53 / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
P30 CA016058/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Proto-Oncogene Proteins c-jun; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; EC 2.7.1.-/MELK protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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