TY - JOUR
T1 - A CK2-Dependent Mechanism for Degradation of the PML Tumor Suppressor
AU - Scaglioni, Pier Paolo
AU - Yung, Thomas M.
AU - Cai, Lu Fan
AU - Erdjument-Bromage, Hediye
AU - Kaufman, Andrew J.
AU - Singh, Bhuvanesh
AU - Teruya-Feldstein, Julie
AU - Tempst, Paul
AU - Pandolfi, Pier Paolo
N1 - Funding Information:
We thank Drs. Rosa Bernardi, Zhenbang Chen, Takahiro Maeda, Michele Pagano, Lorenzo Pinna, Andrea Alimonti, and Xuejun Jiang for sharing reagents and advice. We are grateful to Drs. Harold E. Varmus and William Pao for providing the CC10-rtTA and Tet-op-K-Ras transgenic mice. We thank Tulio Matos, Vincent Mahi, and Lynne Lacomis for technical assistance and Pauline Bonner for pathology data management. This work was supported by NIH grant R01 CA71692 to P.P.P. and NCI Cancer Center Support Grant P30 CA08748 to P.T. P.P.S. received support from the ASCO YIA, the CALGB Oncology Fellows Award, the Charles A. Dana Foundation, the Michael and Ethel L. Cohen Foundation, the Steps for Breath Foundation, and NIH K08 grant CA112325-01.
PY - 2006/7/28
Y1 - 2006/7/28
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2006.05.041
DO - 10.1016/j.cell.2006.05.041
M3 - Article
C2 - 16873060
AN - SCOPUS:33746208870
SN - 0092-8674
VL - 126
SP - 269
EP - 283
JO - Cell
JF - Cell
IS - 2
ER -