The Genes Encoding Human Protein Kinase CK2 and Their Functional Links

Abstract

Abstract Protein kinase CK2 is a Ser⧸Thr phosphotransferase that occurs ubiquitously among eukaryotes. It is pleiotropic, vital, and highly conserved. CK2 is a tetramer composed of two catalytic (α) and two regulatory (β) subunits. Both subunits may occur in isoforms and both may play roles independent of the holoenzymes they form. Humans express α, α′, and β subunits. The human genome contains four CK2 loci at different chromosomes, enclosing three active genes and a pseudogene. This chapter reviews the chromosomal location, structural organization, and expressional control of the genes. It shows that CK2's conservation can also be recognized at the nucleic acid level, that the three active genes have features in common, and that some of these are appropriate for a coordinate transcriptional regulation. In particular, an identical Ets1 double motif that cross-talks to multiple Sp1 (and other) sites is present in the α and β gene promoters, and CK2 holoenzyme but not CK2α phosphorylates Sp1, resulting in a loss of DNA binding. This is compatible with a negative feedback control according to which expression of α and β genes leads to an increased holoenzyme level and thus phosphorylation, which, in turn, decreases transcription. As a consequence, constant transcript levels of both genes are expected to adjust. In human cultured cells, this is indeed the case, independent of their respective proliferation or differentiation status. The chapter also provides an overview of functional links of the CK2 genes to cell-cycle-regulated genes. Based on comparative genome-wide transcript profiles of Saccharomyces cerevisiae wild-type and CK2 mutant strains, CK2 is shown to be involved in transcription regulation of various genes related to cell-cycle control, including genes encoding cyclins and components of spindle pole body formation and dynamics. Strikingly, most of the affected genes lack common elements in their promoters and expression of a large group of genes encoding chromatin remodeling factors is altered, compatible with the idea that CK2 plays a role in the global process of transcription-related chromatin remodeling. In addition, functional links of CK2 are seen to diverse metabolic and nutritional supply pathways, including MET genes responsible for methionine synthesis, and the PHO gene group responsible for phosphate maintenance, which, interestingly, is uncoupled from its central cyclin-Cdk control upon CK2 perturbation.