A CK2-dependent mechanism for degradation of the PML tumor suppressor.
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.
Scaglioni
Pier Paolo
PP
Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Yung
Thomas M
TM
Cai
Lu Fan
LF
Erdjument-Bromage
Hediye
H
Kaufman
Andrew J
AJ
Singh
Bhuvanesh
B
Teruya-Feldstein
Julie
J
Tempst
Paul
P
Pandolfi
Pier Paolo
PP
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016147:Genes, Tumor Suppressor; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006388:Hemagglutinins / Q000737:chemistry; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D000071156:Promyelocytic Leukemia Protein; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D034741:RNA, Small Interfering / Q000494:pharmacology; D017384:Sequence Deletion; D012694:Serine / Q000737:chemistry / Q000378:metabolism; D013012:Sorbitol / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015533:Transcriptional Activation; D014230:Triazoles / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C405354:4,5,6,7-tetrabromobenzotriazole; D004791:Enzyme Inhibitors; D006388:Hemagglutinins; D007976:Leupeptins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D021122:Protein Subunits; D034741:RNA, Small Interfering; D014157:Transcription Factors; D014230:Triazoles; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C485184:enhanced green fluorescent protein; C070576:PML protein, human; D049452:Green Fluorescent Proteins; D012694:Serine; D013012:Sorbitol; D047390:Casein Kinase II; D048051:p38 Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde