A CK2-dependent mechanism for degradation of the PML tumor suppressor Journal Article
| Authors: | Scaglioni, P. P.; Yung, T. M.; Cai, L. F.; Erdjument-Bromage, H.; Kaufman, A. J.; Singh, B.; Teruya-Feldstein, J.; Tempst, P.; Pandolfi, P. P. |
| Article Title: | A CK2-dependent mechanism for degradation of the PML tumor suppressor |
| 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. © 2006 Elsevier Inc. All rights reserved. |
| Keywords: | controlled study; human tissue; protein phosphorylation; human cell; sequence deletion; nonhuman; ubiquitin; animal cell; mouse; animals; mice; animal tissue; apoptosis; enzyme inhibition; proteasome endopeptidase complex; amino acid substitution; serine; carcinoma, non-small-cell lung; lung neoplasms; neoplasm proteins; cell line; animal experiment; animal model; rna, small interfering; lung cancer; in vivo study; enzyme activation; enzyme activity; cell line, tumor; phosphorylation; carcinogenesis; mice, transgenic; transcription factors; nuclear proteins; cancer inhibition; ubiquitination; amino acid sequence; molecular sequence data; enzyme inhibitors; tumor suppressor proteins; cell line, transformed; green fluorescent proteins; protein structure, tertiary; protein subunits; triazoles; nih 3t3 cells; genes, tumor suppressor; promyelocytic leukemia protein; leupeptins; sorbitol; p38 mitogen-activated protein kinases; trans-activation (genetics); casein kinase ii; hemagglutinins |
| Journal Title: | Cell |
| Volume: | 126 |
| Issue: | 2 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2006-07-28 |
| Start Page: | 269 |
| End Page: | 283 |
| Language: | English |
| DOI: | 10.1016/j.cell.2006.05.041 |
| PUBMED: | 16873060 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 101" - "Export Date: 4 June 2012" - "CODEN: CELLB" - "Source: Scopus" |
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