Regulation of cell cycle and cell death are critical for normal cellular proliferation, tissue homeostasis, animal development, and the pathogenesis of human diseases such as cancer. Irregularities in cell cycle and cell death may result in tumorigenesis. In this dissertation, I describe my studies of a novel gene C53, which we found to play pivotal roles in cell cycle and cell death. First, C53 suppresses the G2/M DNA damage checkpoint via inhibiting the activation and kinase activity of checkpoint kinase 1 and checkpoint kinase 2. When treated with genotoxins, cells overexpressing C53 cannot adopt G2 arrest; instead they proceed into mitosis and subsequently die during mitosis. Depletion of C53 leads to sustained G2 arrest and reduces cell death from genotoxins. C53 also regulates mitotic entry during unperturbed cell cycle. Overexpression of C53 leads to unscheduled Cdk1 activation and uneven chromatin condensation, while C53 depletion causes delays in Cdk1 activation and mitotic entry. Second, C53 plays important roles in various stages of mitosis. C53 depletion causes many mitotic defects, including inability to separate centrosomes, mono-polar spindle, rosette-like chromosome arrangement, chromosome lagging, incomplete cytokinesis, and irregularly shaped daughter nuclei. Interestingly, most of these defects resemble those caused by Plk1 depletion. Further studies revealed C53 and Plk1 co-localize with each other at various stages of M phase. C53 interacts with the kinase domain of Plk1 and is a Plk1 substrate. Plk1-mediated phosphorylation of C53 may be important for its functions during M phase. Third, C53 is a caspase substrate, with three caspase cleavage sites sequentially cleaved during apoptosis. Cleavage of C53 into C53-C1 promotes etoposide-induced cell death. In addition, overexpression of C53-C3 caused nuclear deformities. Taken together, these findings demonstrate important functions of C53 during cell cycle and cell death, and provide valuable information for future studies of this novel gene

Last modified

• 05/09/2018

Creator

• Hai Jiang

DOI

• https://doi.org/10.21985/N2GH5X

Subject

• Integrated Graduate Program in the Life Sciences

Keyword

• Mitosis
• Cell Cycle
• G2/M checkpoint
• Cell Death
• C53

Date created

• 2006-12-12

Resource type

• Dissertation

Rights statement

• In Copyright