CK2 mediates phosphorylation and ubiquitin-mediated degradation of the PML tumor suppressor.
The PML tumor suppressor controls growth suppression, induction of apoptosis, and cellular senescence. PML loss occurs frequently in hematopoietic and solid tumors. PML loss often correlates with tumor progression. Casein kinase 2 (CK2) is a stress-activated serine/threonine protein kinase that is oncogenic and frequently overexpressed in human tumor of multiple histological origins. In addition, CK2 overexpression due to gene amplification has been reported to be an adverse prognostic factor in non-small cell lung cancer. At the 5th International Conference on Protein Kinase CK2 in Padova, Italy, we reviewed our recent findings that PML undergoes ubiquitin/proteasome-mediated degradation in immortalized and tumor derived cell lines. PML degradation depends on direct CK2 phosphorylation of PML Ser517. PML mutants that are resistant to CK2 phosphorylation display increased tumor suppressive functions in assays measuring apoptosis, replicative senescence, and in xenograft models. More significantly, CK2 pharmacological inhibition enhances PML tumor suppressive property. These data identify a key post-translational mechanism that controls PML protein levels in cancer cells and suggest that CK2 inhibitors may be beneficial anti-cancer drugs.
Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8852, USA. pier.scaglioni@utsouthwestern.edu
P P
PP
Scaglioni
T M
TM
Yung
S
S
Choi
S C
SC
Choi
C
C
Baldini
G
G
Konstantinidou
P P
PP
Pandolfi
D000595:Amino Acid Sequence; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D000071156:Promyelocytic Leukemia Protein; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013816:Thermodynamics; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C070576:PML protein, human; D047390:Casein Kinase II; D048051:p38 Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex