A CK2-dependent mechanism for degradation of the PML tumor suppressor.
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.
Pubmed ID: 16873060 RIS Download
Amino Acid Sequence | Amino Acid Substitution | Animals | Apoptosis | Carcinoma, Non-Small-Cell Lung | Casein Kinase II | Cell Line | Cell Line, Transformed | Cell Line, Tumor | Enzyme Activation | Enzyme Inhibitors | Genes, Tumor Suppressor | Green Fluorescent Proteins | Hemagglutinins | Humans | Leupeptins | Lung Neoplasms | Mice | Mice, Transgenic | Molecular Sequence Data | NIH 3T3 Cells | Neoplasm Proteins | Nuclear Proteins | Phosphorylation | Promyelocytic Leukemia Protein | Proteasome Endopeptidase Complex | Protein Structure, Tertiary | Protein Subunits | RNA, Small Interfering | Sequence Deletion | Serine | Sorbitol | Transcription Factors | Transcriptional Activation | Triazoles | Tumor Suppressor Proteins | Ubiquitin | p38 Mitogen-Activated Protein Kinases