Interdisciplinary Graduate Program
Program in Molecular Medicine
First Thesis Advisor
Joel D. Richter, Ph.D.
Cell Aging, RNA-Binding Proteins, Repressor Proteins, NF-kappa B, Inflammation
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.
Ivshina, M. Role of CPEB in Senescence and Inflammation: A Dissertation. (2010). University of Massachusetts Medical School. GSBS Dissertations and Theses. Paper 501. DOI: 10.13028/fdzp-7b75. https://escholarship.umassmed.edu/gsbs_diss/501
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