Authors
Ivshina, MariaFaculty Advisor
Joel D. Richter, Ph.D.Academic Program
Interdisciplinary Graduate ProgramUMass Chan Affiliations
Program in Molecular MedicineDocument Type
Doctoral DissertationPublication Date
2010-07-28Keywords
Cell AgingRNA-Binding Proteins
Repressor Proteins
NF-kappa B
Inflammation
Amino Acids, Peptides, and Proteins
Biochemistry, Biophysics, and Structural Biology
Cell and Developmental Biology
Cells
Nucleic Acids, Nucleotides, and Nucleosides
Pathological Conditions, Signs and Symptoms
Metadata
Show full item recordAbstract
Cytoplasmic polyadenylation element-binding protein (CPEB) is a sequence-specific RNA-binding protein that promotes polyadenylation-induced translation. While a CPEB knockout (KO) mouse is sterile but overtly normal, embryo fibroblasts derived from this mouse (MEFs) do not enter senescence in culture as do wild-type MEFs, but instead are immortal. Exogenous CPEB restores senescence in the KO MEFs and also induces precocious senescence in wild-type MEFs. CPEB cannot stimulate senescence in MEFs lacking the tumor suppressors p53, p19ARF, or p16INK4A; however, the mRNAs encoding these proteins are unlikely targets of CPEB since their expression is the same in wild-type and KO MEFs. Conversely, Ras cannot induce senescence in MEFs lacking CPEB, suggesting that it may lie upstream of CPEB. One target of CPEB regulation is myc mRNA, whose unregulated translation in the KO MEFs may cause them to bypass senescence. Thus, CPEB appears to act as a translational repressor protein to control myc translation and resulting cellular senescence. CPEB is a sequence-specific RNA binding protein that regulates cytoplasmic polyadenylation-induced translation. We report here that CPEB KO mice are hypersensitive to LPS-induced endotoxic shock, which correlates with elevated serum levels of the proinflammatory cytokines IL-6, IL-8 and IL-12. Peritoneal macrophages from the KO mice, as well as a CPEB-depleted macrophage cell line, not only secrete more IL-6 than control cells in response to LPS, but also have prolonged retention of NFϰB in the nucleus, which is responsible for elevated IL-6 transcription. The amount of nuclear NFϰB correlates with reduced levels of IϰBα, which is hyperphosphorylated and rapidly degraded. Collectively, these data suggest that CPEB deficiency enhances the inflammatory response via delayed resolution of NFϰB signaling.DOI
10.13028/fdzp-7b75Permanent Link to this Item
http://hdl.handle.net/20.500.14038/31837Rights
Copyright is held by the author, with all rights reserved.ae974a485f413a2113503eed53cd6c53
10.13028/fdzp-7b75