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A novel, non-apoptotic role for Scythe/BAT3: a functional switch between the pro- and anti-proliferative roles of p21 during the cell cycle.

dc.contributor.advisor Wang, Xiao-Fan
dc.contributor.advisor Chikaraishi, Dona
dc.contributor.advisor MacAlpine, David
dc.contributor.advisor Kreuzer, Kenneth
dc.contributor.advisor Haase, Steve
dc.contributor.author Yong, Sheila T.
dc.coverage.spatial United States
dc.date.accessioned 2012-01-10T15:57:17Z
dc.date.issued 2012
dc.identifier.uri https://hdl.handle.net/10161/4958
dc.description.abstract Scythe/BAT3 is a member of the BAG protein family whose role in apoptosis, a form of programmed cell death, has been extensively studied. However, since the developmental defects observed in Bat3‐null mouse embryos cannot be explained solely by defects in apoptosis, I investigated whether BAT3 is also involved in regulating cell‐cycle progression. Using a stable‐inducible Bat3‐knockdown cellular system, I demonstrated that reduced BAT3 protein level causes a delay in both the G1/S transition and G2/M progression. Concurrent with these changes in cell‐cycle progression, I observed a reduction in the turnover and phosphorylation of the CDK inhibitor p21. p21 is best known as an inhibitor of DNA replication; however, phosphorylated p21 has also been shown to promote G2/M progression. Additionally, I observed that the p21 turnover rate was also reduced in Bat3‐knockdown cells released from G2/M synchronization. My findings indicate that in Bat3‐knockdown cells, p21 continues to be synthesized during cell‐cycle phases that do not normally require p21, resulting in p21 protein accumulation and a subsequent cell‐cycle delay. Finally, I showed that BAT3 co‐localizes with p21 during the cell cycle and is required for the translocation of p21 from the cytoplasm to the nucleus during the G1/S transition and G2/M progression. My study reveals a novel, non‐apoptoticrole for BAT3 in cell‐cycle regulation. By maintaining low p21 protein level during G1/S transition, BAT3 counteracts the inhibitory effect of p21 on DNA replication and thus enables the cells to progress from G1 into S phase. Conversely, during G2/M progression, BAT3 facilitates p21 phosphorylation, an event that promotes G2/M progression. BAT3 modulates these pro‐ and anti‐proliferative roles of p21 at least in part by regulating the translocation of p21 between the cytoplasm and nucleus of the cells to ensure proper functioning and regulation of p21 in the appropriate intracellular compartments during different cell‐cycle phases.
dc.language eng
dc.subject Apoptosis
dc.subject Blotting, Western
dc.subject Bone Neoplasms
dc.subject Cell Cycle
dc.subject Cell Proliferation
dc.subject Cyclin-Dependent Kinase Inhibitor p21
dc.subject DNA Replication
dc.subject Flow Cytometry
dc.subject Fluorescent Antibody Technique
dc.subject Humans
dc.subject Molecular Chaperones
dc.subject Osteosarcoma
dc.subject Phosphorylation
dc.subject RNA, Small Interfering
dc.subject Tumor Cells, Cultured
dc.title A novel, non-apoptotic role for Scythe/BAT3: a functional switch between the pro- and anti-proliferative roles of p21 during the cell cycle.
dc.type Dissertation
dc.department Molecular Cancer Biology
duke.embargo.months 24
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/22761665
pubs.organisational-group Duke
pubs.organisational-group Duke
pubs.organisational-group School of Medicine
pubs.organisational-group Duke
pubs.organisational-group School of Medicine
pubs.organisational-group Basic Science Departments
pubs.organisational-group Duke
pubs.organisational-group School of Medicine
pubs.organisational-group Basic Science Departments
pubs.organisational-group Pharmacology & Cancer Biology
pubs.organisational-group Duke
pubs.organisational-group School of Medicine
pubs.organisational-group Institutes and Centers
pubs.organisational-group Duke
pubs.organisational-group School of Medicine
pubs.organisational-group Institutes and Centers
pubs.organisational-group Duke Cancer Institute
pubs.publication-status Published


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