Abstract
The PML tumor suppressor controls key pathways for growth suppression, induction of apoptosis, and cellular senescence. PML loss occurs frequently in human tumors through unknown posttranslational mechanisms. Casein kinase 2 (CK2) is oncogenic and frequently upregulated in human tumors. Here we show that CK2 regulates PML protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at Ser517. Consequently, PML mutants that are resistant to CK2 phosphorylation display increased tumor-suppressive functions. In a faithful mouse model of lung cancer, we demonstrate that Pml inactivation leads to increased tumorigenesis. Furthermore, CK2 pharmacological inhibition enhances the PML tumor-suppressive property in vivo. Importantly, we found an inverse correlation between CK2 kinase activity and PML protein levels in human lung cancer-derived cell lines and primary specimens. These data identify a key posttranslational mechanism that controls PML protein levels and provide therapeutic means toward PML restoration through CK2 inhibition.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Amino Acid Substitution
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Animals
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Apoptosis
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Carcinoma, Non-Small-Cell Lung / enzymology
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / pathology
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Casein Kinase II / antagonists & inhibitors
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Casein Kinase II / genetics
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Casein Kinase II / metabolism*
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Cell Line
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Cell Line, Transformed
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Cell Line, Tumor
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Genes, Tumor Suppressor*
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Green Fluorescent Proteins / metabolism
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Hemagglutinins / chemistry
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Humans
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Leupeptins / pharmacology
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Lung Neoplasms / enzymology
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Lung Neoplasms / genetics
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Lung Neoplasms / pathology
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Mice
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Mice, Transgenic
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Molecular Sequence Data
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NIH 3T3 Cells
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / chemistry
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Neoplasm Proteins / physiology
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Nuclear Proteins / physiology
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Phosphorylation
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Promyelocytic Leukemia Protein
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Proteasome Endopeptidase Complex / metabolism
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Protein Structure, Tertiary
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Protein Subunits
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RNA, Small Interfering / pharmacology
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Sequence Deletion
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Serine / chemistry
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Serine / metabolism
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Sorbitol / pharmacology
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / chemistry
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription Factors / physiology
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Transcriptional Activation
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Triazoles / pharmacology
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Tumor Suppressor Proteins / antagonists & inhibitors
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Tumor Suppressor Proteins / chemistry
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Tumor Suppressor Proteins / physiology
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Ubiquitin / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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4,5,6,7-tetrabromobenzotriazole
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Enzyme Inhibitors
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Hemagglutinins
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Leupeptins
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Neoplasm Proteins
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Nuclear Proteins
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Pml protein, mouse
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Promyelocytic Leukemia Protein
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Protein Subunits
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RNA, Small Interfering
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Transcription Factors
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Triazoles
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Tumor Suppressor Proteins
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Ubiquitin
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enhanced green fluorescent protein
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PML protein, human
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Green Fluorescent Proteins
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Serine
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Sorbitol
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Casein Kinase II
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p38 Mitogen-Activated Protein Kinases
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde