University of Rochester, Ph.D., Biology, 1979 Georgia State University, M.S., Biology, 1974 Duke University, B.A., English, 1969

The secondary modification of proteins by reversible phosphorylation is a major mechanism of protein regulation in eukaryotic cells. The protein kinases and phosphatases that catalyze this reversible modification often constitute integral components of signal transduction cascades that mediate both intracellular homeostasis and extracellular signalling. Interference with the activity of these enzymes, either biochemically or genetically, potentially results in altered cell function and disease. As one example, protein phosphorylation plays a pivotal role in both cell cycle regulation and growth control, and mutation of the protein kinases or phosphatases (or their regulators) involved in these processes often leads to unregulated cell proliferation and cancer. Casein kinase II (CKII) is a highly conserved Ser/Thr protein kinase that is ubiquitous among eukaryotic organisms. Observations from a number of laboratories suggest a role for this enzyme in human cancer: 1) CKII phosphorylates a broad spectrum of endogenous substrates, including known oncoproteins and tumor suppressors, 2) CKII activity is elevated in rapidly dividing normal cells, transformed cells in culture, and solid human tumors, and 3) dysregulated expression of CKII in lymphocytes of transgenic mice results in the stochastic production of lymphomas and, in combination with overexpression of c-myc, in the production of leukemia. Unfortunately, neither the mechanism of regulation nor the physiological role of CKII has been defined in any system. My laboratory is using biochemical, molecular, genetic, cell biological, and genomic approaches to define the function and regulation of CKII in the budding yeast Saccharomyces cerevisiae. My laboratory has purified yeast CKII to homogeneity, characterized the subunit composition and biochemical function of the purified enzyme in vitro, isolated the genes encoding each of the four enzyme subunits, constructed null and conditional mutations of these genes, characterized the resulting phenotypes, and isolated multicopy suppressors of some of these mutants. The results reveal that CKII is essential for viability in S. cerevisiae and required for diverse cellular functions, including cell cycle progression in both G1 and G2/M, maintenance of cell polarity, ion homeostasis, and gene expression. Among the genes identified via genetic interaction are a kinase-specific chaperone required for cell cycle progression (CDC37) and a gene pair intimately involved in cell polarity (ZDS1,2). We are currently employing genomic and proteomic strategies, such as transcriptional profiling and biochemical genomics, in order to define the global function of CKII. The results obtained in the genetically tractable yeast system should yield parallel insights into the physiological role of CKII in higher systems, including man. Given the observations relating CKII to cancer, the results have potential for diagnosis and/or treatment of human disease.

Bandhakavi, S., McCann, R. O., Hanna, D. E., and Glover C. V. C. 2003. Genetic interactions among ZDS1,2, CDC37, and protein kinase CK2 in Saccharomyces cerevisiae. FEBS Lett. 554: 295-300. Bandhakavi, S., McCann, R. O., Hanna, D. E., and Glover C. V. C. 2003. A positive feedback loop between protein kinase CKII and Cdc37 promotes the activity of multiple protein kinases. J. Biol. Chem. 278: 2829-2836. Zhao, W., Bidwai, A. P., and Glover, C. V. C. 2002. Interaction of casein kinase II with ribosomal protein L22 of Drosophila melanogaster. Biochem. Biophys. Res. Commun. 298: 60-66. Ackermann, K., Waxmann, A., Glover, C. V. C., Pyerin, W. 2001. Genes targeted by protein kinase CK2: A genome-wide expression array analysis in yeast. Mol. Cell. Biochem. 227: 59-66. Dotan, I., Ziv, E., Dafni, N., Beckman, J. S., McCann, R. O., Glover, C. V. and Canaani, D. 2001. Functional conservation between the human, nematode, and yeast CK2 cell cycle genes. Biochem. Biophys. Res. Commun. 288: 603-609. Bidwai, A. P., Saxena, A., Zhao, W., McCann, R. O., and Glover, C. V. C. 2000. Multiple, closely spaced alternative 5' exons in the DmCKIIb gene of Drosophila melanogaster. Mol. Cell Biol. Res. Commun. 3: 283-291. Tenney, K.A. and Glover, C. V. C. 1999. Transcriptional regulation of the S. cerevisiae ENA1 gene by casein kinase II. Mol. Cell. Biochem. 191: 161-167. Bidwai, A. P., Zhao, W., and Glover, C. V. C. 1999. A gene located at 56F1-2 in Drosophila melanogaster encodes a novel b-like subunit of casein kinase II. Mol. Cell Biol. Res. Commun., 1: 21-28. Brewer, J. M., Glover, C. V. C., Holland, M. J., and Lebioda, L. 1998. Significance of the enzymatic properties of yeast S39A enolase to the catalytic mechanism. Biochem. Biophys. Acta 1383: 351-355. Glover III, C. V. C. 1998. On the physiological role of casein kinase II in Saccharomyces cerevisiae. Prog. Nucl. Acid Res. Mol. Biol. 57: 95-133. Rethinaswamy, A., Birnbaum, M. J., and Glover, C. V. C. 1998. Temperature-sensitive mutations of the CKA1 gene reveal a role for casein kinase II in maintenance of cell polarity in Saccharomyces cerevisiae. J. Biol. Chem. 273: 5869-5877. Narcisi, E. M., Glover, C. V. C., Fechheimer, M. 1998. Fibrillarin, a conserved pre-ribosomal RNA processing protein of Giardia. J. Euk. Microbiol., 45: 105-111. Brewer, J. M., Glover, C. V. C., Holland, M. J., and Lebioda, L. 1997. Effect of site-directed mutagenesis of His373 of yeast enolase on some of its physical and enzymatic properties. Biochem. Biophys. Acta 1340: 88-96. Hanna, D. E., Rethinaswamy, A., and Glover, C. V. C. 1995. Casein kinase II is required for cell cycle progression during G1 and G2/M in Saccharomyces cerevisiae. J. Biol. Chem. 270: 25905-25914. Sangadala, V. S., Glover, C. V. C., Robson, R. L., Holland, M. J., Lebioda, L., and Brewer, J. M. 1995. Preparation by site-directed mutagenesis of the E211Q mutant of yeast enolase 1. Biochem. Biophys. Acta. 1251: 23-31. Glover, C. V. C. 1995. ScCK2 Casein kinase II (S. cerevisiae) in The Protein Kinase FactsBook (Hardie, D. G. and Hanks, S. K., eds.), Academic Press, London, Vol. I, pp. 246-248. Glover, C. V. C. 1995. DmCK2 Casein kinase II (D. melanogaster) in The Protein Kinase FactsBook (Hardie, D. G. and Hanks, S. K., eds.), Academic Press, London, Vol. I, pp. 243-245. Bidwai, A. P., Reed, J. C., and Glover, C. V. C. 1995. Cloning and disruption of CKB1, the gene encoding the 38 kDa b subunit of Saccharomyces cerevisiae casein kinase II (CKII): Deletion of CKII regulatory subunits elicits a salt-sensitive phenotype. J. Biol. Chem. 270: 10395-10404. Glover, C. V. C., Bidwai, A. P., and Reed, J. C. 1994. Structure and function of Saccharomyces cerevisiae casein kinase II. Cell. Mol. Biol. Res. 40: 481-488. Reed, J. C., Bidwai, A. P., and Glover, C. V. C. 1994. Cloning and disruption of CKB2, the gene encoding the 32-kDa regulatory b'-subunit of Saccharomyces cerevisiae casein kinase II. J. Biol. Chem. 269: 18192-18200. Bidwai, A. P., Reed, J. C., and Glover, C. V. C. 1994. Casein kinase II of Saccharomyces cerevisiae contains two distinct regulatory subunits, b and b'. Arch. Biochem. Biophys. 309: 348-355. Brewer, J. M., Robson, R. L., Glover, C. V. C., Holland, M. J., and Lebodia, L. 1993. Preparation and characterization of the E168Q site-directed mutant of yeast enolase 1. Prot. Str. Func. Gen. 17: 426-434. Bidwai, A. P., Reed, J. C. and Glover, C. V. C. 1993. The phosphorylation of calmodulin by the catalytic subunit of casein kinase II is inhibited by the regulatory subunit. Arch. Biochem. Biophys. 300: 265-270. Bidwai, A. P., Hanna, D. E. and Glover, C. V. C. 1992. Purification and characterization of casein kinase II (CKII) from Dcka1 Dcka2 Saccharomyces cerevisiae rescued by Drosophila CKII subunits: The free catalytic subunit of casein kinase II is not toxic in vivo. J. Biol. Chem. 267: 18790-18796. Cardenas, M. E., Dang, Q., Glover, C. V. C., and Gasser, S. M. 1992. Casein kinase II phosphorylates the eukaryotic-specific C-terminal domain of topoisomerase II in vivo. EMBO J., 11: 1785-1796.