The Function of Calcium/calmodulin Dependent Protein Kinase Ii in Cell Cycle Regulation
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چکیده
Ca/Calmodulin-dependent protein kinase II (CamKII) is a multifunctional enzyme that is activated by increases in intracellular Ca. CaMKII is expressed in all tissues but is most abundant in the brain. Diversity in subunit composition and Ca sensitivity permit the coordination of multiple cellular functions including muscle contraction, synaptic vesicle release, proliferation and differentiation. The factors allowing CaMKII to mediate a broad spectrum of cellular processes with such precision are just beginning to be understood. Proximity of Ca signals and the CaMKII activator Calmodulin (CaM), as well as CaMKII subunit composition influence the processes that CaMKII will mediate. As with other kinases, intracellular localization is thought to be a major factor in substrate selection. This dissertation presents two perspectives on CaMKII function. First, in light of the diversity and complexity of CaMKII function, investigation of compartmentalized CaMKII will provide more insight into the physiological condtions under which it operates. Targeted CaMKII genes also have the potential to be therapeutic agents. For example, CaMKII activates a chloride conductance at the plasma membrane of secretory epithelia. Plasma membrane targeted CaMKII may provide stimulation of this chloride channel that is adequate compensation for the defects in fluid secretion characteristic of cystic fibrosis (CF). CF is a lethal hereditary disease characterized by the accumulation of thick mucus secretions from polarized epithelial cells lining the airways and gastrointestinal tract, which impede organ function. The feasibility of targeting CaMKII to specific subcellular locations was investigated in HeLa cells with three CaMKII gene constructs each with a different plasma membrane targeting motif. The data show that plasma membrane targeting of CaMKII is feasible when the targeting motif is attached to the N-terminus of the protein, but not the Cterminus. The second part of this dissertation examines the role of CaMKII at the G2/M transition of the cell cycle. Previous reports show that CaMKII is required for progression from G2 into mitosis. Expression of autonomous CaMKII prevents this transition. Cell lines that display stable expression of an autonomous mutant CaMKII (CaMKIIT286D), reveal experience a delayed mitosis. It is likely that this delay is the result of autonomous CaMKII activation of a cell cycle checkpoint protein that impedes mitosis. Acknowledgements I would like to thank my mother Wanda Beauman, my father Johannes Beauman, my sisters Charlene and Shaunda Beauman my grandparents, aunts, uncles and cousins. Your love, support and encouragement have been an invaluable source of inspiration and motivation to me. I would like to thank my fiancé Steven I. Iyoha. You are my heart and I am so blessed to have had you as my cheerleader and consoler and celebrant. I am grateful to the members of my thesis committee, Dr. John Dedman, chairman, Dr. M. Begoña Campos-Naciff, Dr. Raymund Pun, Dr. Sue Heffelfinger Dr. Robert Banks and Dr. Marcia Kaetzel. Many thanks for sharing your time, experience and insights. I would like to dedicate this dissertation to my grandfather Walter Cleaver Greer Jr. December 25, 1921-March 27, 2003
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