CPEB regulation of human cellular senescence, energy metabolism, and p53 mRNA translation
Open accessAbstract
Cytoplasmic polyadenylation element-binding protein (CPEB) stimulates polyadenylation and translation in germ cells and neurons. Here, we show that CPEB-regulated translation is essential for the senescence of human diploid fibroblasts. Knockdown of CPEB causes skin and lung cells to bypass the M1 crisis stage of senescence; reintroduction of CPEB into the knockdown cells restores a senescence-like phenotype. Knockdown cells that have bypassed senescence undergo little telomere erosion. Surprisingly, knockdown of exogenous CPEB that induced a senescence-like phenotype results in the resumption of cell growth. CPEB knockdown cells have fewer mitochondria than wild-type cells and resemble transformed cells by having reduced respiration and reactive oxygen species (ROS), normal ATP levels, and enhanced rates of glycolysis. p53 mRNA contains cytoplasmic polyadenylation elements in its 3′ untranslated region (UTR), which promote polyadenylation. In CPEB knockdown cells, p53 mRNA has an abnormally short poly(A) tail and a reduced translational efficiency, resulting in an ∼50% decrease in p53 protein levels. An shRNA-directed reduction in p53 protein by about 50% also results in extended cellular life span, reduced respiration and ROS, and increased glycolysis. Together, these results suggest that CPEB controls senescence and bioenergetics in human cells at least in part by modulating p53 mRNA polyadenylation-induced translation.
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In early embryos, longer poly(A)-tail lengths cause more efficient translation.
“We favor this last possibility because it agrees with the known importance of cytoplasmic polyadenylation for activating genes in maturing oocytes8,21,22 and early embryos23,24 of Xenopus and certain other vertebrate contexts25–30.”
From Poly(A)-tail profiling reveals an embryonic switch in translational control (2014) · cites this paper as [29]
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- Authors
- Burns, D. M., & Richter, J. D.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- ORCID
- Richter, Joel D.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2008-12-15
- Volume
- 22
- Issue
- 24
- Pages
- 3449-3460
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC2607074
- OpenAlex
- W2138670947
- Cited by
- 134
- References
- 59
- Citations by year
- 2025: 5 · 2024: 7 · 2023: 4 · 2022: 11 · 2021: 7 · 2020: 7 · 2019: 4 · 2018: 4 · 2017: 7 · 2016: 10 · 2015: 7 · 2014: 10 · 2013: 9 · 2012: 17
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship@UMassChan (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health (DK32520)
- National Institute on Aging (R01AG030323, AG30323)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 32520, P30DK032520)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- CPEB, cellular senescence, cytoplasmic polyadenylation, 3' untranslated region, poly(A) tail, energy metabolism, mitochondrial respiration, reactive oxygen species, glycolysis, telomere shortening, diploid fibroblasts, skin cells, lung cells, translational regulation
- MeSH terms
- Animals, Base Sequence, Cell Line, Cells, Cultured, Energy Metabolism, Humans, Molecular Sequence Data, RNA, Messenger, Time Factors, Transcription Factors, Genes, p53, Sequence Alignment, Cellular Senescence, Mice, Knockout, Gene Expression Regulation, Developmental, mRNA Cleavage and Polyadenylation Factors, Mice, Gene Knockdown Techniques
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