p53 isoforms Δ133p53 and p53β are endogenous regulators of replicative cellular senescence
Open accessAbstract
The finite proliferative potential of normal human cells leads to replicative cellular senescence, which is a critical barrier to tumour progression in vivo. We show that the human p53 isoforms Delta133p53 and p53beta function in an endogenous regulatory mechanism for p53-mediated replicative senescence. Induced p53beta and diminished Delta133p53 were associated with replicative senescence, but not oncogene-induced senescence, in normal human fibroblasts. The replicatively senescent fibroblasts also expressed increased levels of miR-34a, a p53-induced microRNA, the antisense inhibition of which delayed the onset of replicative senescence. The siRNA (short interfering RNA)-mediated knockdown of endogenous Delta133p53 induced cellular senescence, which was attributed to the regulation of p21(WAF1) and other p53 transcriptional target genes. In overexpression experiments, whereas p53beta cooperated with full-length p53 to accelerate cellular senescence, Delta133p53 repressed miR-34a expression and extended the cellular replicative lifespan, providing a functional connection of this microRNA to the p53 isoform-mediated regulation of senescence. The senescence-associated signature of p53 isoform expression (that is, elevated p53beta and reduced Delta133p53) was observed in vivo in colon adenomas with senescent phenotypes. The increased Delta133p53 and decreased p53beta isoform expression found in colon carcinoma may signal an escape from the senescence barrier during the progression from adenoma to carcinoma.
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Colon adenoma-derived samples have elevated expression of p16INK4a, HP1γ, and focal γH2AX expression, indicating enhanced DNA damage.
“colon adenoma- derived samples also have elevated expression of p16 INK4a , HP1γ (an H3K9me3- enriched senescence- associated heterochromatin focus- promoting scaffold that connects H3K9 methyltransferases to Rb as another binding partner), and focal γH2AX expression, indicating enhanced DNA damage 87,89 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [89]
The colon-adenoma passage (labeled Abstract; page not provided) reports significantly higher p16INK4A expression in adenomas than in non-adenoma or normal colon tissue. Our copy does not report elevated HP1γ or focal γH2AX expression in those samples, so it does not support the claim of enhanced DNA damage on that basis. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn cultured normal human fibroblasts, p53β speeds up and Δ133p53 suppresses replicative senescence.
“In normal human fibroblasts cultured in vitro, p53β accelerates and Δ133p53 represses replicative senescence (15), consistent with their modes of functional interaction with p53FL.”
From p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes (2013) · cites this paper as [15]
Premalignant colon adenomas with pathologically induced senescent cells show elevated p53β and reduced Δ133p53, and loss of this pattern is linked to malignant progression.
“Premalignant colon adenomas with pathologically induced senescent cells in vivo also showed a specific profile of p53 isoform expression (i.e., elevated levels of p53β and reduced levels of Δ133p53), the loss of which was associated with malignant progression to colon carcinomas (15).”
From p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes (2013) · cites this paper as [15]
The regulatory mechanisms for p53 isoform expression may be conserved between CD8+ T lymphocytes and fibroblasts.
“The regulatory mechanisms for the p53 isoform expression may be conserved in CD8 + T lymphocytes (present study) and fibroblasts (15).”
From p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes (2013) · cites this paper as [15]
Δ133p53 undergoes autophagic breakdown, whereas p53FL and p53β are broken down by the proteasome.
“The autophagic degradation of Δ133p53 is in contrast to the proteasome-mediated degradation of p53FL and p53β (15)”
From p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes (2013) · cites this paper as [15]
Δ133p53 dominantly inhibits the transcriptional activity of p53FL for p53 target genes, including p53-repressed genes.
“Since Δ133p53 dominant-negatively inhibits the transcriptional activity of p53FL for p53 target genes, including p53-repressed genes (15), and CD28 contains a p53 response element within its intron 1 (p53FamTag; http://p53famtag.ba.itb.cnr.it/),”
From p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes (2013) · cites this paper as [15]
These p53 isoforms control tumorigenesis in vivo through both tumor-cell-intrinsic and tumor-cell-extrinsic effects.
“suggests that these p53 isoforms regulate tumorigenesis in vivo in both tumor cellautonomous and non-autonomous manners.”
From p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes (2013) · cites this paper as [15]
The Δ133p53 siRNA 133si-2 specifically knocks down Δ133p53.
“Of 2 siRNA oligonucleotides previously shown to specifically knock down Δ133p53 in normal human fibroblasts (15), 133si-2 (5′-CUUGUGCCCUGACUUUCAA[dT][dT]-3′) was used here because it caused more efficient knockdown via nucleofection.”
From p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes (2013) · cites this paper as [15]
Δ133p53 transcriptionally activates CD28 mRNA expression.
“these data suggest a mechanism by which Δ133p53, which lacks the transactivation domain (14), transcriptionally activates CD28 mRNA expression.”
From p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes (2013) · cites this paper as [15]
Δ133p53 acts as a dominant-negative blocker of p53FL.
“our previous finding that Δ133p53 functions as a dominant-negative inhibitor of p53FL (15)”
From p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes (2013) · cites this paper as [15]
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Alterations of MicroRNAs Contribute to Colon Carcinogenesis
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- Authors
- Fujita, K., Mondal, A. M., Horikawa, I., Nguyen, G. H., Kumamoto, K., Sohn, J. J., Bowman, E. D., Mathe, E. A., Schetter, A. J., Pine, S. R., Ji, H., Vojtesek, B., Bourdon, J.-C., Lane, D. P., & Harris, C. C.
- Affiliations
- National Institutes of Health (US)
- Inserm (FR)
- Corresponding author
- Harris, Curtis C.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2009-08-23
- Volume
- 11
- Issue
- 9
- Pages
- 1135-1142
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC2802853
- OpenAlex
- W1524571013
- Cited by
- 336
- References
- 40
- Citations by year
- 2026: 16 · 2025: 21 · 2024: 18 · 2023: 15 · 2022: 23 · 2021: 28 · 2020: 18 · 2019: 17 · 2018: 27 · 2017: 13 · 2016: 18 · 2015: 18 · 2014: 15 · 2013: 15 · 2012: 22
- FWCI
- 16.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research UK
- National Institutes of Health
- Medical Research Council
- National Cancer Institute (Z01BC010878, ZIABC010878, ZIABC005795, Z01BC005480, Z01BC005795)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- p53 isoforms, Δ133p53, miR-34a, p21, colonic adenoma, colon cancer, oncogene-induced senescence, senescence escape, carcinogenesis, microRNA regulation
- MeSH terms
- Colonic Neoplasms, Humans, Mutation, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Cellular Senescence, Protein Isoforms, MicroRNAs, Cell Line, Tumor, Gene Knockdown Techniques
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