Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2007 May;8(5):497-503.
doi: 10.1038/sj.embor.7400937. Epub 2007 Mar 30.

Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence

Wilfredo Cosme-Blanco  1 , Mei-Feng Shen, Alexander J F Lazar, Sen Pathak, Guillermina Lozano, Asha S Multani, Sandy Chang
Affiliations

Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence

Wilfredo Cosme-Blanco et al. EMBO Rep. 2007 May.

Abstract

Dysfunctional telomeres induce p53-dependent cellular senescence and apoptosis, but it is not known which function is more important for tumour suppression in vivo. We used the p53 ( R172P ) knock-in mouse, which is unable to induce apoptosis but retains intact cell-cycle arrest and cellular senescence pathways, to show that spontaneous tumorigenesis is potently repressed in Terc -/- p53 ( R172P ) mice. Tumour suppression is accompanied by global induction of p53, p21 and the senescence marker senescence-associated-beta-galactosidase. By contrast, cellular senescence was unable to suppress chemically induced skin carcinomas. These results indicate that suppression of spontaneous tumorigenesis by dysfunctional telomeres requires the activation of the p53-dependent cellular senescence pathway.

PubMed Disclaimer

Figures

Figure 1
Figure 1
TRF2 ΔBΔM induces telomere dysfunction and cellular senescence in p53 P/P primary mouse embryonic fibroblasts. (A) BrdU incorporation of p53 +/+, p53 P/P and p53 −/− MEFs at day 4 after infection with H-RasV12, TRF2ΔBΔM or empty (vector) retrovirus. The percentage of BrdU positive cells relative to controls is indicated. Error bars represent standard error of the mean (s.e.m.). (B) Prominent SA-β-gal staining was observed only in p53 P/P but not in p53 −/− MEFs infected with Myc-tagged TRF2 ΔBΔM or H-RasV12. (C) Quantitation of the percentage of SA-β-gal positive cells. Error bars represent s.e.m. (D) Immunoblots of lysates from p53 +/+, p53 −/− and p53 P/P MEFs. Cells were infected with either Myc-TRF2 ΔBΔM , H-RasV12 or vector and proteins were detected with the indicated antibodies. (E) Colocalization of DDR foci to dysfunctional telomeres (arrowheads) in p53 P/P MEFs 48 h after infection with TRF2 ΔBΔM : telomeres (TRITC, red; left), γ-H2AX (FITC, green; middle) and merged (right). Arrowheads indicate telomere dysfunction induced foci. (F) End-to-end chromosomal fusions were detected after infection with TRF2 ΔBΔM , but not with vector, in p53 P/P and p53 −/− MEFs. (E,F) Arrowheads point to sites of fusions. BrdU, bromodeoxyuridine; DDR, DNA damage response; FITC, fluorescein isothiocyanate; MEF, mouse embryonic fibroblast; SA-β-gal, senescence-associated-β-galactosidase; TRF2, telomere repeat-binding factor 2; TRITC, tetramethyl rhodamine isothiocyanate.
Figure 2
Figure 2
Dysfunctional telomeres do not initiate an apoptotic response in iG1 Terc −/− p53 P/P mice. (A) Bone marrow metaphases isolated from iG1 Terc −/− p53 P/P mice show chromosome end-to-end fusions (arrow), whereas Terc +/− p53 P/P metaphases showed minimal abnormalities. (B) Quantitation of cytogenetic aberrations in bone marrow from mice of the indicated genotypes. Error bars represent s.e.m. (C) Anaphase bridges (indicated by arrows) in intestines of iG1 Terc −/− p53 P/+ and iG1 Terc −/− p53 P/P mice. (D) Quantitation of anaphase bridges in intestines of mice of the indicated genotypes. Error bars represent s.e.m. (E) TUNEL staining of testes of the indicated genotypes. (F) TUNEL staining of intestines of the indicated genotypes. (G) Quantitation of the number of apoptotic cells present in intestinal crypts of the indicated genotypes. Error bars represent s.e.m. iG1, first intergenerational mating; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling.
Figure 3
Figure 3
Kaplan–Meier analysis of mouse cohorts. Tumour incidence (A,C) and overall survival (B,D) of mice of the indicated genotypes are shown. The number of tumours identified (t), the total number of mice (n) and the P-values (calculated using the log-rank test) are indicated. Note the near-complete tumour suppression in iG1 p53 P/+, iG1 p53 P/P and iG1 p53 +/+ mice. Deletion of p53 reduced the lifespan of iG1 mice owing to increased tumour formation. iG1, first intergenerational mating; NS, statistically not significant.
Figure 4
Figure 4
Telomere dysfunction induces cellular senescence in vivo. (A) Immunostaining with p53 antibody detected staining in intestinal crypts of iG1 iG1 Terc −/− p53 P/P and Terc −/− p53 P/+ mice, but not in Terc +/− p53 P/P and Terc +/− p53 P/+ mice. (B) Immunostaining with p21 antibody detected staining in intestinal crypts of mice of the indicated genotypes. (C) Robust SA-β-gal activity detected in tissues from iG1 Terc −/− p53 P/+ mice (top) but not in tissues from iG1 Terc −/− p53 +/+ mice (bottom). (D) End-to-end chromosomal fusions (indicated by arrows) and telomere signal-free ends in an iG1 Terc −/− p53 P/P lymphoma. iG1, first intergenerational mating.
Figure 5
Figure 5
Skin papillomas in mice of the indicated genotypes. (A) Total number of papillomas of the indicated sizes plotted against the number of weeks after carcinogen treatment. The genotypes of treated mice are indicated. Asterisks indicate the week when a mouse died. n: total number of treated mice; t: number of mice with tumours. (B) Increased anaphase bridge index in iG1 Terc −/− p53 P/P papillomas. (C) Immunohistochemistry of carcinogen-treated iG1 Terc −/− p53 P/P mouse (left) show high p21, p53 and Ki-67 positivity in the nuclei of keratinocytes. Upper panel: squamous papilloma. Lower panel: invasive SCC. iG1, first intergenerational mating; SCC; squamous-cell carcinomas.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L, DePinho RA (2000) Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406: 641–645 - PubMed
    1. Bartkova J et al. (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434: 864–870 - PubMed
    1. Bartkova J et al. (2006) Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 2444: 633–637 - PubMed
    1. Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, Greider CW (1997) Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91: 25–34 - PubMed
    1. Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B, Stein H, Dorken B, Jenuwein T, Schmitt CA (2005) Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436: 660–665 - PubMed

Publication types

Substances