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.
authors.affiliation: Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Scaglioni
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Yung
authors.forename: Lu Fan
authors.initials: LF
authors.lastname: Cai
authors.forename: Hediye
authors.initials: H
authors.lastname: Erdjument-Bromage
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kaufman
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Singh
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.forename: Paul
authors.initials: P
authors.lastname: Tempst
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: 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
chemical_list: 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