Abstract
The carboxyl-terminal modulator protein (CTMP) has been identified as a negative regulator of protein kinase B/Akt. Aberrant Akt signaling is frequently observed in glioblastomas, the most common and most malignant glial brain tumors. Because loss of CTMP function and/or expression may remove the inhibitory effects on Akt and promote tumorigenesis, we studied 93 primary glioblastomas and nine glioblastoma cell lines for CTMP deletion, mutation, promoter hypermethylation, and mRNA expression. None of the tumors or cell lines had CTMP-homozygous deletions or coding sequence mutations. However, CTMP mRNA expression was lower by at least 50% relative to non-neoplastic brain tissue in 37 (40%) glioblastomas and six (67%) glioma cell lines. Reduced CTMP mRNA levels were closely associated with hypermethylation of the CTMP promoter. Furthermore, treatment of CTMP-hypermethylated A172 glioma cells with the demethylating agent 5-aza-2'-deoxycytidine and the histone deacetylase inhibitor trichostatin A resulted in partial demethylation of the CTMP promoter and increased CTMP mRNA expression. Thus, epigenetic downregulation of CTMP transcription is a common aberration in glioblastomas.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Antibiotics, Antineoplastic / pharmacology
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Antimetabolites, Antineoplastic / pharmacology
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Azacitidine / analogs & derivatives*
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Azacitidine / pharmacology
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Carrier Proteins / drug effects
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism*
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Cell Line, Tumor
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DNA Methylation / drug effects
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Decitabine
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Down-Regulation / drug effects
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Gene Deletion
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Gene Expression Regulation, Neoplastic / drug effects
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Glioblastoma / metabolism*
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Humans
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Hydroxamic Acids / pharmacology
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Membrane Proteins / drug effects
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism*
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Mutation
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Thiolester Hydrolases
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Transcription, Genetic*
Substances
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Adaptor Proteins, Signal Transducing
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Antibiotics, Antineoplastic
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Antimetabolites, Antineoplastic
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Carrier Proteins
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Hydroxamic Acids
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Membrane Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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trichostatin A
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Decitabine
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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THEM4 protein, human
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Thiolester Hydrolases
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Azacitidine