Abstract
The Carboxy-Terminal Modulator Protein (CTMP) protein was identified as a PKB inhibitor that binds to its hydrophobic motif. Here, we report mitochondrial localization of endogenous and exogenous CTMP. CTMP exhibits a dual sub-mitochondrial localization as a membrane-bound pool and a free pool of mature CTMP in the inter-membrane space. CTMP is released from the mitochondria into the cytosol early upon apoptosis. CTMP overexpression is associated with an increase in mitochondrial membrane depolarization and caspase-3 and polyADP-ribose polymerase (PARP) cleavage. In contrast, CTMP knock-down results in a marked reduction in the loss of mitochondrial membrane potential as well as a decrease in caspase-3 and PARP activation. Mutant CTMP retained in the mitochondria loses its capacity to sensitize cells to apoptosis. Thus, proper maturation of CTMP is essential for its pro-apoptotic function. Finally, we demonstrate that CTMP delays PKB phosphorylation following cell death induction, suggesting that CTMP regulates apoptosis via inhibition of PKB.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / physiology*
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Amino Acid Sequence
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins / chemistry
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / physiology*
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Cell Line
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Cysteine Proteinase Inhibitors / pharmacology
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Cytosol / metabolism
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Enzyme Activation
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Humans
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Membrane Proteins / chemistry
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Membrane Proteins / genetics
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Membrane Proteins / physiology*
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Mitochondria / physiology*
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Molecular Sequence Data
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Phosphorylation
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Protein Processing, Post-Translational
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Protein Sorting Signals / physiology
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Protein Transport
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / physiology
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RNA, Small Interfering / pharmacology
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Recombinant Fusion Proteins / physiology
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Sequence Alignment
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Sequence Homology
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Solubility
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Thiolester Hydrolases
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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Cysteine Proteinase Inhibitors
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Membrane Proteins
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Protein Sorting Signals
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Recombinant Fusion Proteins
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Proto-Oncogene Proteins c-akt
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THEM4 protein, human
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Thiolester Hydrolases