A CK2-Dependent Mechanism for PML Degradation upon Cellular and Oncogenic Stress

The PML tumor suppressor controls key pathways for growth suppression, induction of apoptosis and cellular senescence. PML loss occurs frequently in hematopoietic and solid tumors through unknown post-translational mechanisms. PML loss often correlates with tumor progression. Casein kinase 2 (CK2) is a stress activated serine/threonine protein kinase that is oncogenic and frequently over-expressed in human tumor of multiple histological origins including non Hodgkin’s lymphomas, acute leukemias and multiple myeloma. In addition, CK2 over-expression due to gene amplification has been reported to be a powerful adverse prognostic factor in non-small cell lung cancer. We recently reported that PML undergoes ubiquitin/proteasome mediated degradation in immortalized and tumor derived cell lines (Cell. 2006, 126:269). PML degradation depends on direct CK2 phosphorylation of Ser517 in the PML C-terminal degron. PML mutants that are resistant to CK2 phosphorylation display increased tumor suppressive functions in assays measuring apoptosis, replicative senescence and in xenograft models. Now, we report the identification and characterization of novel cellular and oncogenic stress signaling pathways that control the CK2/PML degradation pathway. This analysis allowed us to determine the signaling cascades upstream of CK2. In addition, we found an inverse correlation between CK2 kinase activity and PML protein levels in cancer-derived cell lines and primary specimens. Significantly, CK2 pharmacological inhibition enhances PML tumor suppressive property in vivo and in vitro. These data identify a key post-translational mechanism that controls PML protein levels and provide therapeutic means toward PML restoration through CK2 inhibition. The implications of these new findings during the physiologic response to cellular stress and in the pathogenesis of hemopoietic malignancies will be discussed at the meeting.