Abstract
Protein kinase CK2 (also known as Caseine Kinase II) is an ubiquitous Ser/Thr protein kinase present in both the nucleus and cytoplasm of cells, targeting several key enzymes, growth factor receptors, transcription factors and cytoskeletal proteins. It is not only a key player in regulating cellular growth and proliferation, but also behaves as a potent suppressor of apoptosis. CK2 has been frequently found to be deregulated (mostly hyperactivated) in all cancers, prostate cancer being prominent of them. In the recent past, tumor suppressor PML (promyelocytic leukemia) has been shown to be a target of phosphorylation by CK2. This phosphorylation promotes the ubiquitin-mediated proteasomal degradation of PML thereby effectively curbing its role as a tumor suppressor. Among many others, PML has also been established to mediate its tumor suppressive role by mitigating the inactivation of active AKT (pAKT) inside the nucleus by assembling a dephosphorylating platform for nuclear pAKT. One of the immediate consequences, of this inactivation is the stabilization of FOXO3a, another well-established tumor suppressor, inside the nucleus and its downstream activities. Here, we propose a novel signaling axis apexed by deregulated CK2, dismantling the association of PML and PHLPP2 (we also report PHLPP2 to be a novel interacting partner of PML inside the nucleus), ultimately leading to the inactivation and nuclear exclusion of FOXO3a, thereby downregulating p21/p27/Bim in which degradation of PML and the concomitant stabilization of pAKT plays a cardinal part.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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Carcinoma / genetics*
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Carcinoma / metabolism
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Carcinoma / pathology
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Casein Kinase II / genetics*
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Casein Kinase II / metabolism
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Cell Line, Tumor
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Cell Movement
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Cell Nucleus / genetics
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Cell Nucleus / metabolism
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Cyclin-Dependent Kinase Inhibitor p27 / genetics
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism
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Forkhead Box Protein O3
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Forkhead Transcription Factors / genetics*
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Forkhead Transcription Factors / metabolism
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Gene Expression Regulation, Neoplastic*
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Humans
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Phosphoprotein Phosphatases / genetics
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Phosphoprotein Phosphatases / metabolism
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Promyelocytic Leukemia Protein
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Prostatic Neoplasms / genetics*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering / genetics
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Signal Transduction
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Transcription, Genetic
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / metabolism
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p21-Activated Kinases / genetics
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p21-Activated Kinases / metabolism
Substances
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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FOXO3 protein, human
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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Membrane Proteins
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Nuclear Proteins
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Promyelocytic Leukemia Protein
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Proto-Oncogene Proteins
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RNA, Small Interfering
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Transcription Factors
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Tumor Suppressor Proteins
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PML protein, human
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Cyclin-Dependent Kinase Inhibitor p27
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Casein Kinase II
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Proto-Oncogene Proteins c-akt
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p21-Activated Kinases
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PHLPP2 protein, human
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Phosphoprotein Phosphatases