Activation of protein kinase CK2 attenuates FOXO3a functioning in a PML-dependent manner: implications in human prostate cancer

• Published in: Cell death & disease Vol. 4; no. 3; p. e543
• Main Authors: Chatterjee, A, Chatterjee, U, Ghosh, M K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2013; Springer Nature B.V; Nature Publishing Group
• Subjects: Antibodies; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; Biochemistry; Biomedical and Life Sciences; Carcinoma - genetics; Carcinoma - metabolism; Carcinoma - pathology; Casein Kinase II - genetics; Casein Kinase II - metabolism; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Movement; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Forkhead Box Protein O3; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene Expression Regulation, Neoplastic; Humans; Immunology; Life Sciences; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Original; original-article; p21-Activated Kinases - genetics; p21-Activated Kinases - metabolism; Phosphoprotein Phosphatases - genetics; Phosphoprotein Phosphatases - metabolism; Promyelocytic Leukemia Protein; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; RNA, Small Interfering - genetics; Signal Transduction; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; PML; CK2; FOXO3a
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2013.63

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.