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A CK2-dependent mechanism for degradation of the PML tumor suppressor.

Cell | Jul 28, 2006

http://www.ncbi.nlm.nih.gov/pubmed/16873060

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

Mesh terms: 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 | 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