Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

p53 isoforms Δ133p53 and p53β are endogenous regulators of replicative cellular senescence

Abstract

The finite proliferative potential of normal human cells leads to replicative cellular senescence, which is a critical barrier to tumour progression in vivo1,2,3. We show that the human p53 isoforms Δ133p53 and p53β4 function in an endogenous regulatory mechanism for p53-mediated replicative senescence. Induced p53β and diminished Δ133p53 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 microRNA5,6,7,8,9, the antisense inhibition of which delayed the onset of replicative senescence. The siRNA (short interfering RNA)-mediated knockdown of endogenous Δ133p53 induced cellular senescence, which was attributed to the regulation of p21WAF1 and other p53 transcriptional target genes. In overexpression experiments, whereas p53β cooperated with full-length p53 to accelerate cellular senescence, Δ133p53 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 p53β and reduced Δ133p53) was observed in vivo in colon adenomas with senescent phenotypes10,11. The increased Δ133p53 and decreased p53β isoform expression found in colon carcinoma may signal an escape from the senescence barrier during the progression from adenoma to carcinoma.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Replicative senescence-associated changes in expression of endogenous p53 isoforms.
Figure 2: Endogenous miR-34a is a regulator of replicative senescence.
Figure 3: Knockdown of endogenous Δ133p53 induces cellular senescence.
Figure 4: Overexpression of p53β induces senescence and overexpression of Δ133p53 extends the replicative lifespan.
Figure 5: p53 isoform expression profiles in colon carcinogenesis in vivo.

Similar content being viewed by others

References

  1. Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Collado, M., Blasco, M. A. & Serrano, M. Cellular senescence in cancer and aging. Cell 130, 223–233 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Halazonetis, T. D., Gorgoulis, V. G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Bourdon, J. C. et al. p53 isoforms can regulate p53 transcriptional activity. Genes Dev. 19, 2122–2137 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bommer, G. T. et al. p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr. Biol. 17, 1298–1307 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Chang, T. C. et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol. Cell 26, 745–752 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. He, L. et al. A microRNA component of the p53 tumour suppressor network. Nature 447, 1130–1134 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Raver-Shapira, N. et al. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol. Cell 26, 731–743 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Tazawa, H., Tsuchiya, N., Izumiya, M. & Nakagama, H. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc. Natl. Acad. Sci. USA 104, 15472–15477 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dai, C. Y. et al. p16INK4a expression begins early in human colon neoplasia and correlates inversely with markers of cell proliferation. Gastroenterology 119, 929–942 (2000).

    Article  CAS  PubMed  Google Scholar 

  11. Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Harley, C. B., Vaziri, H., Counter, C. M. & Allsopp, R. C. The telomere hypothesis of cellular aging. Exp. Gerontol. 27, 375–382 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. Chen, J. et al. p53 isoform Δ113p53 is a p53 target gene that antagonizes p53 apoptotic activity via BclxL activation in zebrafish. Genes Dev. 23, 278–290 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Webley, K. et al. Posttranslational modifications of p53 in replicative senescence overlapping but distinct from those induced by DNA damage. Mol. Cell. Biol. 20, 2803–2808 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yang, Q. et al. Functional diversity of human protection of telomeres 1 isoforms in telomere protection and cellular senescence. Cancer Res. 67, 11677–11686 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. van Steensel, B., Smogorzewska, A. & de Lange, T. TRF2 protects human telomeres from end-to-end fusions. Cell 92, 401–413 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Brown, J. P., Wei, W. & Sedivy, J. M. Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277, 831–834 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Herbig, U., Jobling, W. A., Chen, B. P., Chen, D. J. & Sedivy, J. M. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21CIP1, but not p16INK4a. Mol. Cell 14, 501–513 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Yamakuchi, M., Ferlito, M. & Lowenstein, C. J. miR-34a repression of SIRT1 regulates apoptosis. Proc. Natl. Acad. Sci. USA 105, 13421–13426 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wei, J. S. et al. The MYCN oncogene is a direct target of miR-34a. Oncogene 27, 5204–5213 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kumamoto, K. et al. Nutlin-3a activates p53 to both down-regulate inhibitor of growth 2 and up-regulate mir-34a, mir-34b, and mir-34c expression, and induce senescence. Cancer Res. 68, 3193–3203 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kortlever, R. M., Higgins, P. J. & Bernards, R. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nature Cell Biol. 8, 877–884 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Wajapeyee, N., Serra, R. W., Zhu, X., Mahalingam, M. & Green, M. R. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132, 363–374 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Parrinello, S., Coppe, J. P., Krtolica, A. & Campisi, J. Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J. Cell Sci. 118, 485–496 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Gjoerup, O. V. et al. Surveillance mechanism linking Bub1 loss to the p53 pathway. Proc. Natl. Acad. Sci. USA 104, 8334–8339 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kidokoro, T. et al. CDC20, a potential cancer therapeutic target, is negatively regulated by p53. Oncogene 27, 1562–1571 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Tang, X., Milyavsky, M., Goldfinger, N. & Rotter, V. Amyloid-β precursor-like protein APLP1 is a novel p53 transcriptional target gene that augments neuroblastoma cell death upon genotoxic stress. Oncogene 26, 7302–7312 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Rozan, L. M. & El-Deiry, W. S. p53 downstream target genes and tumor suppression: a classical view in evolution. Cell Death Differ. 14, 3–9 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Yin, Y., Tainsky, M. A., Bischoff, F. Z., Strong, L. C. & Wahl, G. M. Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell 70, 937–948 (1992).

    Article  CAS  PubMed  Google Scholar 

  30. Hastie, N. D. et al. Telomere reduction in human colorectal carcinoma and with ageing. Nature 346, 866–868 (1990).

    Article  CAS  PubMed  Google Scholar 

  31. O'Sullivan, J. et al. Telomere length in the colon declines with age: a relation to colorectal cancer? Cancer Epidemiol. Biomarkers Prev. 15, 573–577 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Horikawa, I., Suzuki, M. & Oshimura, M. An amino-terminally truncated p53 protein expressed in a human choriocarcinoma cell line, CC1. Hum. Mol. Genet. 4, 313–314 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. Sengupta, S. et al. BLM helicase-dependent transport of p53 to sites of stalled DNA replication forks modulates homologous recombination. EMBO J. 22, 1210–1222 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Blagosklonny, M. V. et al. p53 inhibits hypoxia-inducible factor-stimulated transcription. J. Biol. Chem. 273, 11995–11998 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Autrup, H., Harris, C. C., Schwartz, R. D., Trump, B. F. & Smith, L. Metabolism of 1, 2-dimethylhydrazine by cultured human colon. Carcinogenesis 1, 375–380 (1980).

    Article  CAS  PubMed  Google Scholar 

  40. Schetter, A. J. et al. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299, 425–436 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank M. Serrano, M. Tainsky, M. Oshimura, G. Hannon, T. de Lange and J. Khan for cells and reagents, X. Wang for helpful discussions, E. Spillare for continuous support and E. Michalova for technical assistance. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute (NCI). B.V. was supported by the grants from the Grant Agency of the Czech Republic (GACR; number 301/08/1468) and the Internal Grant Agency of Health of Czech Republic (IGA MZ CR; number NS/9812-4). J.C.B. was supported by Breast Cancer Campaign, Cancer-Research UK (CRUK) and the Institut National de la Sante et de la Recherche Medicale (Inserm). D.L. is a Gibb fellow of CRUK. H. J. participated in the NIH Summer Internship Program.

Author information

Authors and Affiliations

Authors

Contributions

K.F., A.M.M., I.H., G.H.N., K.K., J.J.S., E.D.B., A.J.S., S.R.P. and H.J. performed experiments. E.A.M. provided expertise on statistical data analysis. B.V., J.-C.B. and D.P.L. provided essential reagents and suggestions. K.F., I.H. and C.C.H. coordinated the study and wrote the manuscript. C.C.H. was responsible for the overall project. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Curtis C. Harris.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 1279 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fujita, K., Mondal, A., Horikawa, I. et al. p53 isoforms Δ133p53 and p53β are endogenous regulators of replicative cellular senescence. Nat Cell Biol 11, 1135–1142 (2009). https://doi.org/10.1038/ncb1928

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1928

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing