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p53 Deficiency Rescues the Adverse Effects of Telomere Loss and Cooperates with Telomere Dysfunction to Accelerate Carcinogenesis
Open accessAbstract
Maintenance of telomere length and function is critical for the efficient proliferation of eukaryotic cells. Here, we examine the interactions between telomere dysfunction and p53 in cells and organs of telomerase-deficient mice. Coincident with severe telomere shortening and associated genomic instability, p53 is activated, leading to growth arrest and/or apoptosis. Deletion of p53 significantly attenuated the adverse cellular and organismal effects of telomere dysfunction, but only during the earliest stages of genetic crisis. Correspondingly, the loss of telomere function and p53 deficiency cooperated to initiate the transformation process. Together, these studies establish a key role for p53 in the cellular response to telomere dysfunction in both normal and neoplastic cells, question the significance of crisis as a tumor suppressor mechanism, and identify a biologically relevant stage of advanced crisis, termed genetic catastrophe.
Checked 2026-10-06 · 12 references not checked yet
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TL;DR
In telomerase-deficient (mTR−/−) mice, critically short telomeres activate p53, and deleting p53 rescues the resulting apoptosis and cell-cycle arrest — but only during early "crisis." Loss of telomere function and p53 deficiency cooperate to initiate transformation, while telomerase reconstitution mainly benefits later stages of tumorigenesis.
Key findings
- Critical telomere shortening activates p53: p53 protein was detectable in G6 mTR−/− testis but not in mTR+/+ or G6 mTR−/− p53−/− littermates; >80% of G4 and G6 MEFs stained positive for p53 at passage 6 versus 21% of mTR+/+ MEFs. p21CIP1/WAF1 rose 3- to 4-fold in G6 versus G2 mTR−/− p53+/+ MEFs, and p53-dependent CAT reporter activity increased ~2-fold.
- p53 loss rescued telomere-dysfunction phenotypes early but not late: 15% of G4–G6 mTR−/− mice (86/565) were p53−/− versus 26% of G7–G8 mice (24/91) (p = 0.015); all G5 mTR−/− p53−/− testes had normal histology, but 3 of 7 G6 and all five G7–G8 samples showed germ cell depletion. G6 mTR−/− p53−/− MEFs showed a 3-fold increase in chromosome fusions (1.65, SD 2.59 vs 0.42, SD 0.71 per metaphase; p = 0.012), with no change in telomere length (75% reduction regardless of p53 status).
- Telomere dysfunction cooperated with p53 deficiency to initiate transformation: adding mTR suppressed Myc/RAS focus formation in G6 mTR−/− p53−/− MEFs, but mTR-transfected foci had higher subcloning efficiency (23/26, 89%) than vector foci (19/32, 59%; p = 0.018). Tumor formation in SCID mice was similar between groups.
- The authors propose dividing crisis into p53-dependent "early crisis" and p53-independent "genetic catastrophe," questioning crisis as a tumor suppressor mechanism.
Methods
- Mouse genetics: mTR+/− mice crossed with p53+/− mice to generate successive generations (G1–G8) of mTR−/− animals with p53+/+, +/−, and −/− genotypes in a mixed WW6/C57BL/6 background; p53 status maintained heterozygous during matings.
- Cellular/organ assays: immunoblotting and immunohistochemistry for p53 and p21, pG13CAT reporter assays, testis histology with TUNEL, BrdU/propidium iodide FACS cell-cycle profiles, flow FISH telomere length, and metaphase spreads for chromosome fusions.
- Transformation assays: Myc/RAS cotransfection of early-passage MEFs with empty vector or an mTR genomic fragment, scoring focus formation, subcloning efficiency, and tumor formation after subcutaneous injection into SCID mice.
Limitations
- Stated: the mechanisms by which tumorigenic potential is maintained in late stages of tumorigenesis despite telomere dysfunction "remain to be determined"; whether loss of TRF2 binding, short telomeres, or fusion-bridge-breakage cycles mediate the p53 induction described also remains undetermined.
- Evident from the text: the G7–G8 genotype comparison rests on small numbers (24 of 91 mice), and all mice are in a mixed genetic background, which the authors note required cousin mating to avoid substrains.
- Evident from the text: the transformation data are from cultured MEFs and SCID xenografts, and tumor weights/efficiency between mTR and vector lines were not significantly different, so the in vivo relevance of the initiation advantage is inferred rather than directly demonstrated.
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40 Own interpretation · 39 Own result · 22 Not checked yet · 6 Own method · 4 No basis given
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In the paper
“Correspondingly, the loss of telomere function and p53 deficiency cooperated to initiate the transformation process.”
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In the paper
“Coincident with severe telomere shortening and associated genomic instability, p53 is activated, leading to growth arrest and/or apoptosis.”
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In the paper
“This activity was strictly dependent upon p53, since p53−/− and G6 mTR−/− p53−/− MEF cultures showed only background levels of CAT activity.”
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In the paper
“We found that p53 mediates the adverse effects of critically shortened telomeres.”
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In the paper
“As shown in Figure 3A, DNA content analyses of G6 mTR−/− p53+/+ MEFs revealed a profile consistent with a biphasic block as evidenced by marked accumulation of cells in G1 and G2/M phases.”
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“Indeed, analysis of metaphase spreads derived from G6 mTR−/− p53+/+ MEFs showed a rate of 0.42 (SD 0.71) chromosomal fusions per metaphase, a rate consistent with previous studies (Figure 3D) (Blasco et al. 1997; Greenberg et al. 1999; Rudolph et al. 1999”
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In the paper
“Furthermore, p53-independent cell death becomes a more consistent feature in G7 and G8, since all of the five G7–G8 mTR−/− p53−/− testis samples showed significant germ cell depletion microscopically (Figure 2D).”
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“However, a relative increase in p53−/− mice was evident in G7 and G8 mTR−/− background (24% and 38%, respectively).”
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In the paper
“Gross testis size was consistently rescued to near normal in G6 mTR−/− p53−/− mice compared to G6 mTR−/− p53+/+ littermates (see Figure 2A for representative comparison).”
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In the paper
“Furthermore, loss of telomere function and p53 deficiency can cooperate to enhance transformation.”
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- It may state two separate claims as one. 36
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- Probably not a substantial claim. 16
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Deletion of p53 significantly attenuated the adverse cellular and organismal effects of telomere dysfunction, but only during the earliest stages of genetic crisis.”
plaindirect- Asserted: passes — The authors put it forward as true.
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“In contrast, mTR+/+ p53+/+ MEF cultures demonstrated 35% of cells in S phase and only 13% in G2/M.”
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“In mTR+/+ testis, p53 status did not affect testicular volume or significantly alter the cytoarchitecture of seminiferous tubules (Figure 2A and Figure 2B).”
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In the paper
“Whereas only 21% of the mTR+/+ MEFs at passage 6 stained positive for p53, more than 80% of MEFs derived from G4 and G6 exhibited strong immunoreactivity to p53 (Figure 1B, compare [a] with [b] and [c]).”
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“In male germ cells and lymphocytes, telomere loss elicits a strong apoptotic response, whereas MEFs experience a potent biphasic cell cycle block.”
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- Rests on an assumption: The mTR−/− mouse is a valid model for studying the consequences of telomere loss in vivo.
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In the paper
“Whereas all G5 mTR−/− p53−/− testes exhibited normal histology, 3 of 7 G6 mTR−/− p53−/− samples still showed varying degrees of pathology (Table 1).”
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In the paper
“Accordingly, BrdU incorporation assay showed that 36% of the G6 mTR−/− p53+/+ cells were in G1 phase, 3% were in S phase, and 40% were in G2/M (Figure 3A, top panel).”
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In the paper
“Immunoprecipitation and Western blot analysis readily detected p53 in lysates from G6 mTR−/− testis, but not in lysates derived from age-matched mTR+/+ testis or from G6 mTR−/− p53−/− littermate controls (Figure 1A).”
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In the paper
“This induction of p53 coincides with the dramatic increase in apoptosis (as assessed by TUNEL) and decreased cellularity in the G6 mTR−/− testis (Lee et al. 1998”
What the sources say
- Not checked yetcites Lee et al. 1998 source
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In the paper
“Significantly, loss of p53 rescues the cell cycle arrest in MEFs and the apoptotic elimination of male germ cells.”
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In the paper
“loss of p53 abrogated this block.”
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In the paper
“Significantly, 15% of the G4–G6 mTR−/− mice (86 out of 565 mice) were p53−/− compared to 26% of the G7–G8 mTR−/− mice (24 of 91 mice) (p = 0.015 by Fisher’s two-sided t test) (Figure 1E).”
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In the paper
“By comparison, G6 mTR−/− p53−/− MEFs exhibited 1.65 (SD 2.59) fusions per metaphase, a 3-fold increase (p = 0.012).”
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In the paper
“In the case of MEFs, this arrest occurs in concert with the stabilization and activation of the p53 protein, evident in p53-dependent reporter assays and activation of p21CIP1/WAF1.”
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In the paper
“Similar differences were observed in low-density seeding experiments (data not shown).”
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In the paper
“In human cells, a critical telomere length is eventually reached that induces cellular senescence, thus limiting the replicative capacity of cultured cells at the Hayflick limit (Hayflick and Moorhead 1961”
What the sources say
- Not checked yetcites Hayflick and Moorhead 1961 source
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In the paper
“In primary cells deficient for Rb and p53, continued cellular growth beyond the Hayflick limit results in severe telomere shortening, marked genetic instability, and massive cell death—a period referred to as crisis (Counter et al. 1992”
What the sources say
- Not checked yetcites Counter et al. 1992 source
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In the paper
“Ectopically expressed hTERT maintains telomere length and allows unlimited growth (Bodnar et al. 1998; Counter et al. 1998; Vaziri and Benchimol 1998”
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In the paper
“The notion that telomere function may indeed be required for immortalization is supported by the frequent activation of telomerase or ALT in human cancers (Kim et al. 1994; Bryan et al. 1995”
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In the paper
“The telomere signal that activates this senescent program operates through the RB and p53 pathways, since cell division beyond the Hayflick limit can occur after antisense neutralization (Hara et al. 1991”
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In the paper
“Telomerase is comprised of essential catalytic (telomerase reverse transcriptase [TERT]) and RNA components (telomerase RNA [TR]) (reviewed in Greider 1998”
What the sources say
- Not checked yetcites Greider 1998 source
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In the paper
“Strikingly, as mTR−/− mice advance with age and generation, an increase in cancer incidence is observed presumably due to increased genetic instability caused by telomere shortening, repeated chromosomal fusion-bridge-breakage cycles, and chromosomal loss (Rudolph et al. 1999”
What the sources say
- Not checked yetcites Rudolph et al. 1999 source
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In the paper
“Due to the very long telomeres of Mus musculus, critical reduction in telomere length and chromosomal instability is only seen following extensive passage of mTR−/− cells (Niida et al. 1998”
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In the paper
“The RNA subunit provides the template for telomere repeat synthesis (Greider and Blackburn 1989; Yu et al. 1990”
What the sources say
- Not checked yetcites Greider and Blackburn 1989
- Not checked yetcites Yu et al. 1990
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In the paper
“although immortalization of some epithelial cells requires not only TERT expression but also compromise of the RB pathway (Kiyono et al. 1998”
What the sources say
- Not checked yetcites Kiyono et al. 1998 source
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In the paper
“Although loss of telomere and p53 function facilitates initiation of transformation, the reconstitution of telomerase activity greatly improved the capacity of transformed foci to yield immortal cultures.”
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In the paper
“Because G2 mTR−/− and G6 mTR−/− MEFs both lack telomerase activity, we conclude that telomere shortening or associated chromosome fusions and breakage rather than telomerase deficiency per se signals to p53 and accounts for p21CIP1/WAF1 induction.”
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In the paper
“Thus, the rampant genetic instability of the G7 and G8 mTR−/− p53−/− cells is associated with loss of cell viability despite p53 deficiency, implying that advanced genomic catastrophe gives way to a p53-independent process.”
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The mTR−/− mouse is a valid model for studying the consequences of telomere loss in vivo.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results indicate that telomere dyfunction acts synergistically with p53 deficiency to initiate malignant transformation, presumably by enhancing genetic instability.”
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In the paper
“Continued proliferation in the absence of the p53 checkpoint may lead to an increased loss of telomere sequences and therefore account for the increased frequency of chromosome fusions.”
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For these matings, the p53 status was maintained in the heterozygous state to avoid potential broad genomic effects arising from p53 deficiency.”
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The ability of exogenous telomerase to reduce focus formation in p53 null cells with short dysfunctional telomeres suggests that genetic instability associated with telomere loss can serve as an engine driving initiation of transformation, but only in the absence of functional p53 (Figure 5).”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Focus formation reflects the earliest stages of oncogenic transformation.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Early crisis accounts for efficient germ cell depletion in G6 mTR−/− p53+/+, whereas the altered histology of G7 and G8 mTR−/− p53−/− testis provides experimental support for late crisis.”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The mTR−/− mouse is a valid model for studying the consequences of telomere loss in vivo.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these data indicate that p53 deficiency restores neither telomere length nor function in the telomerase-deficient mouse.”
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“This mating scheme also produced p53+/+ and p53−/− littermate controls for each mTR−/− generation.”
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Telomere shortening in mTR−/− mice results in loss of telomere function and chromosome end-to-end fusion (Blasco et al. 1997; Rudolph et al. 1999”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The observation that mTR expression facilitates subcloning efficiency of Myc/RAS-transformed late-generation mTR−/− cells supports the importance of telomere maintenance mechanisms during later stages of carcinogenesis.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Induction of double strand breaks in DNA by ionizing radiation or genotoxic chemotherapy leads to the rapid stabilization of p53 through phosphorylation of its N terminus (Shieh et al. 1997; Siliciano et al. 1997”
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“Together with previous work, our data indicated that, first, during the early stages of tumorigenesis, cells suffer telomere shortening, and second, that telomerase activation is advantageous primarily in later stages of tumorigenesis.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Many human tumors that are telomerase positive still have short telomeres.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Cells with short telomeres and intact p53-mediated DNA damage responses may be more efficiently “culled” from the population (via apoptosis or arrest); therefore, p53 null cells may accumulate more end-to-end fusions than their p53+/+ counterparts.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Once both telomere function and p53 have been impaired, the fate of the cell is unpredictable and depends on other stochastic genetic changes.”
plainconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“This stabilization results in either cell cycle arrest via transcriptional induction of the p21CIP1/WAF1 CDK inhibitor or apoptosis (reviewed in Levine 1997”
What the sources say
- Not checked yetcites Levine 1997 source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Loss of p53 can circumvent this checkpoint, leading eventually to p53-independent apoptosis, perhaps as a consequence of uncontrolled chromosome fusion-bridge-breakage cycles and progressive genomic instability.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, both the apoptotic response and cell cycle arrest induced by telomere dysfunction are mediated by p53.”
plaindirect- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For telomere length determination of MEFs, littermate MEF cultures were assayed simultaneously to reduce experimental variability.”
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“At least two independent determinations of the same cultures were performed.”
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Day to day variations in the linearity of the flow cytometer were controlled by the use of FITC-labeled fluorescence beads (Flow Cytometry Standards Corporation).”
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Three independent age-matched sets of animals were used.”
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In mTR−/− INK4a−/− mice, it is likely that telomere dysfunction activates p53 via a DNA damage signaling pathway and results in growth arrest or apoptosis, limiting the efficiency of carcinogenesis”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper relies on this without support.
The signals and pathways mediating the cellular responses associated with telomere dysfunction have yet to be defined in mammalian cells.
“The signals and pathways mediating these cellular responses associated with telomere dysfunction have yet to be defined in mammalian cells.”
The paper relies on this without support.
The RAD9 and MEC1 DNA damage response pathways in yeast are similar to the p53 checkpoint in mammalian cells.
“The RAD9 and MEC1 DNA damage response pathways in yeast are thought to be similar to the p53 checkpoint in mammalian cells.”
The paper relies on this without support.
The mTR−/− mouse is a valid model for studying the consequences of telomere loss in vivo.
“The mTR−/− mouse serves as a model to study the consequences of telomere loss in vivo.”
The paper relies on this without support.
Focus formation reflects the earliest stages of oncogenic transformation.
“Focus formation is thought to reflect the earliest stages of oncogenic transformation.”
The paper relies on this without support.
Human cells require inactivation of Rb and/or p53 to bypass the major checkpoint that limits replicative lifespan: cellular senescence.
“Human cells require inactivation of Rb and/or p53 to bypass the major checkpoint that limits replicative lifespan: cellular senescence.”
The paper relies on this without support.
Rb/p53 inactivation allows continued cell division beyond senescence, progressive telomere shortening, and entry into crisis, from which only rare survivors emerge.
“Rb/p53 inactivation allows continued cell division beyond senescence, progressive telomere shortening, and entry into crisis, from which only rare survivors will emerge.”
The paper relies on this without support.
Many human tumors that are telomerase positive still have short telomeres.
“The fact that many human tumors that are telomerase positive still have short telomeres supports the idea that telomerase activation occurs late in tumorigenesis.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Although enabling cellular growth and survival and masking degenerative phenotypes, these mTerc -/ -p53 mutant mice experience a dramatic increase in cancer incidence, shift in tumor spectrum toward epithelial cancers, and accumulation of marked chromosomal aberrations targeting cancerrelevant loci for amplification and deletion (4-6).”
From Ink4a / Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [4]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Specifically, p53 deficiency results in nearcomplete rescue of adverse cellular consequences associated with telomere dysfunction, including cellular growth arrest and apoptosis, progressive organ system atrophy, and physiological compromise.”
From Ink4a / Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [4]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Telomere dysfunction appears to engage the p53-dependent double-stranded break DNA damage pathway.”
From Ink4a / Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [4]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“When the p53 checkpoint is compromised, unchecked genomic instability caused by telomere dysfunction accelerates tumorigenesis as seen in late-generation mTerc -/ -p53 mutant mice (4, 5).”
From Ink4a / Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [4]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“The downstream effector pathways of telomere-induced senescence are largely p53-dependent96, but there may be involvement of the retinoblastoma protein (RB) pathway in some settings97.”
From The telomere syndromes (2012) · cites this paper as [96]
The cited source says what the claim attributes to it.
In the citing paper
“recent reports of the effect of the mTR deletion in different genetic backgrounds (17, 18) suggest that the role of telomerase in cancer development could be highly context dependent (19).”
From Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death (1999) · cites this paper as [18]
In the citing paper
“By contrast, p53 inactivation alone is sufficient to avoid telomere-induced senescence and apoptosis in mice49,50.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [49]
In the citing paper
“In the absence of telomerase, continued cell division results in telomere shortening, loss of ‘capping’ function, and p53 activation12-15.”
From Telomere dysfunction induces metabolic and mitochondrial compromise (2011) · cites this paper as [15]
In the citing paper
“p53 deficiency markedly attenuates the degenerative phenotypes associated with telomere dysfunction, whereas constitutively activated p53 accelerates ageing phenotypes15-18.”
From Telomere dysfunction induces metabolic and mitochondrial compromise (2011) · cites this paper as [15]
In the citing paper
“Critically short telomeres induce cellular and tissue defects through checkpoint signaling pathways that converge on the p53 tumor suppressor protein, a well-known cellular stress sensor that enforces cell cycle arrest or cell death in response to diverse stimuli including activated oncogenes, DNA damage and hypoxia (69)”
From Telomeres and telomerase in cancer (2010) · cites this paper as [69]
In the citing paper
“Importantly, removal of p53 function rescued many of the cellular defects despite the presence of critically short telomeres, including growth arrest in cell culture, testicular atrophy, intestinal and germ cell apoptosis46.”
From Telomere dysfunction and tumour suppression: the senescence connection (2008) · cites this paper as [46]
Citations
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MethodInfluentialExtension of Life-Span by Introduction of Telomerase into Normal Human Cells
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Self-citation
Cited by
Sorted by citations
Items 501–600 of 975
The Connection Between Cell Fate and Telomere
Engin, A. B., & Engin, A. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-49844-3_3 · Cited by 39
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“In particular, chromosomal instability caused by critical shortening of telomeres has been proposed as a trigger of cancer initiation in most epithelial cells (Chin et al., 1999; Artandi and DePinho, 2000).”
How does suppression of IGF-1 signaling by DNA damage affect aging and longevity?
Hinkal, G. W., & Donehower, L. A. (2008) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2008.02.005 · Cited by 33
“Nevertheless, there are some accelerated aging models in Table 1 where inactivation of p53 results in attenuation or rescue of the accelerated aging/senescence phenotypes (Cao et al., 2003; Chin et al., 1999; Varela et al., 2005).”
Kondo, T., Oue, N., Mitani, Y., Kuniyasu, H., Noguchi, T., Kuraoka, K., Nakayama, H., & Yasui, W. (2005) · Oncogene · doi:10.1038/sj.onc.1207832 · Cited by 34
Understanding telomere diseases through analysis of patient-derived iPS cells
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Self-citationCrosstalk between P53 and DNA damage response in ageing
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“Because functional p53 is deleted in the K562 cell line [22] and based on the findings in other model systems [23], we reasoned that intact p53 signaling could be a prerequisite for induction of senescence and/or apoptosis in response to telomerase inhibition–mediated critical telomere shortening and consequently for…”
Telomerase, immortality and cancer
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Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status
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“(Chin et al.,1999) Not investigated.”
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“In late generation Terc null mice, p53 deficiency significantly attenuated cell cycle and reproductive organ defects but not the reduced telomere length, and in mice homozygous for a null allele of the telomere repeat binding factor 1 gene (Terf1), p53 deficiency partially attenuated the early embryonic lethality (Chi…”
Telomere fusion to chromosome breaks reduces oncogenic translocations and tumour formation
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“5696 18wk n=19 t(12;14), t(14;1;14;1) t(13;15), t(13;3), t(2p;19p), t(13;16), t(t(2;19); t(2;14)), t(14;1), t(14;7), t(14;2;14), t(8;14), t(7;14), t(19;2), t(14;8), t(13;4), t(13;2), t(13;18); f(11p;11p), f(15p;19p), f(7p;10p), f(14q;10q), f(7p;14q).”
InfluentialSelf-citationMirjolet, C., Boidot, R., Saliques, S., Ghiringhelli, F., Maingon, P., & Créhange, G. (2015) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2015.02.005 · Cited by 35
“Indeed, there is a higher incidence of certain tumors in telomerase-Knock-Out (KO) mice that harbor p53 mutations [30,31].”
Removing all obstacles: A critical role for p53 in promoting tissue renewal
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“Initial studies indicated that concurrent deficiency in p53 helps attenuate the degenerative pathologies seen in many adult tissues, suggesting that p53 activation detrimentally affects tissue homeostasis following telomere erosion.(16) Additionally, deletion of a cell cycle inhibitor induced by p53, Cdkn1a (p21), alm…”
Lobanova, A., She, R., Pieraut, S., Clapp, C., Maximov, A., & Denchi, E. L. (2017) · Genes & Development · doi:10.1101/gad.295402.116 · Cited by 32
“to be detrimental to various dividing nonneuronal cell types (Lee et al. 1998; Chin et al. 1999; Rudolph et al. 1999; Jacobs and de Lange 2004; Celli and de Lange 2005; Zhang et al. 2006; Minty et al. 2008; Martinez et al. 2014).”
Aging and Neurological Diseases
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“It is known that a reduction in the number of divisions prevents the accumulation of mutations [16].”
Tieing together loose ends: telomere instability in cancer and aging
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Modeling aging and cancer in the telomerase knockout mouse
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Miracco, C., Santi, M. M. D., Schürfeld, K., Santopietro, R., Lalinga, A. V., Fimiani, M., BIAGIOLI, M., Brogi, M., Felice, C. D., Luzi, P., et al. (2002) · British Journal of Dermatology · doi:10.1046/j.1365-2133.2002.04600.x · Cited by 31
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A novel p53 regulator, C16ORF72/TAPR1, buffers against telomerase inhibition
Benslimane, Y., Sánchez‐Osuna, M., Coulombe‐Huntington, J., Bertomeu, T., Henry, D., Huard, C., Bonneil, É., Thibault, P., Tyers, M., & Harrington, L. A. (2021) · Aging Cell · doi:10.1111/acel.13331 · Cited by 30
“In mice with eroded telomeres, p53 deficiency initially rescues the adverse effects of telomere dysfunction on proliferation but then promotes subsequent tumor initiation (Chin et al., 1999).”
BackgroundDown-regulation of p21 contributes to apoptosis induced by HPV E6 in human mammary epithelial cells
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Activation of p53 protein by telomeric (TTAGGG)n repeats
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The TP53 Dependence of Radiation-Induced Chromosome Instability in Human Lymphoblastoid Cells
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Dual roles of telomere dysfunction in initiation and suppression of tumorigenesis
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“On the other hand, loss of p53 function cooperates with dysfunctional telomeres to promote carcinogenesis at the expense of premature aging (Chin et al. 1999).”
Prediagnostic telomere length and risk of B-cell lymphoma-Results from the EPIC cohort study
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“Mouse models 525 that are TERC- and p53-deficient display an increased tumor incidence compared to TERC-526 deficient, p53 wild-type mice (Chin et al., 1999), indicating a role for telomere dysfunction in 527 promoting carcinogenesis.”
BackgroundTumor suppressor mechanisms in immune aging
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The potential roles of p53 signaling reactivation in pancreatic cancer therapy
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“Short telomeres reflect damaged DNA and also trigger a p53-dependent response (57), yet PTRF effects on cellular senescence and SIPS have been described as independent of telomere status (36, 53).”
Vasko, T., Kaifie, A., Stope, M. B., Kraus, T., & Ziegler, P. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18112267 · Cited by 31
“example, the loss of the tumor protein 53 and the activation of telomere maintenance mechanisms [7].”
Replicative senescence in sheep fibroblasts is a p53 dependent process
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Holohan, B., Meyer, T. D., Batten, K. G., Mangino, M., Hunt, S. C., Bekaert, S., Buyzere, M. D., Rietzschel, E. R., Spector, T. D., Wright, W. E., et al. (2015) · Aging Cell · doi:10.1111/acel.12347 · Cited by 28
“This eventually triggers cell growth arrest, termed ‘replicative senescence,’ via an uncapped telomere end recognized by the p53 pathway (Chin et al., 1999).”
The many types of heterogeneity in replicative senescence
Xu, Z., & Teixeira, M. T. (2019) · Yeast · doi:10.1002/yea.3433 · Cited by 29
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“Telomere dysfunction in Terc−/−, p53+/− or Terc−/−, p53−/− cells is associated with a loss of cell cycle checkpoint control in mouse embryonic fibroblasts (MEFs) [27] and the promotion of epithelial tumors in mice [28].”
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Telomeres and telomere dynamics: relevance to cancers of the GI tract
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Take care of your chromosomes lest cancer take care of you
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Self-citationA New Connection at Human Telomeres: Association of the Mre11 Complex with TRF2Preprint
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ZNF365 Promotes Stability of Fragile Sites and Telomeres
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Self-citationLansdorp, P. M. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.943622 · Cited by 27
“Given that most malignant tumors are deficient in p53, the Achilles heel of tumor suppression via telomere erosion in humans is perhaps loss of p53, resulting in failure to impose cell cycle arrest or apoptosis when telomeres are too short (6, 8, 76).”
Functional association between telomeres, oxidation and mitochondria
Moustakli, E., Zikopoulos, A., Sakaloglou, P., Bouba, I., Sofikitis, N., & Georgiou, I. A. (2023) · Frontiers in Reproductive Health · doi:10.3389/frph.2023.1107215 · Cited by 29
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“In addition, the sustained replication of unstable tumor cells with longer TL may allow for somatic evolution, such as the acquisition of mutations that contribute to the emergence of cloneswith enhanced capacity for invasion and metastasis (43, 75, 76).”
BackgroundDifferential Roles of Telomere Attrition in Type I and II Endometrial Carcinogenesis
Akbay, E. A., Contreras, C. M., Perera, S. A., Sullivan, J. P., Broaddus, R. R., Schorge, J. O., Ashfaq, R., Saboorian, H. M., Wong, K., & Castrillón, D. H. (2008) · American Journal Of Pathology · doi:10.2353/ajpath.2008.071179 · Cited by 26
TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts
Brunori, M., Mathieu, N., Ricoul, M., Bauwens, S., Koering, C., de Climens, A. R., Belleville, A., Wang, Q., Puisieux, I., Décimo, D., et al. (2005) · Oncogene · doi:10.1038/sj.onc.1209135 · Cited by 26
Schwartz, J. L., Jordan, R. T., Liber, H. L., Murnane, J. P., & Evans, H. H. (2001) · Genes Chromosomes and Cancer · doi:10.1002/1098-2264(2000)9999:9999 · Cited by 27
Telomere Biology of Human Hematopoietic Stem Cells
Elwood, N. J. (2004) · Cancer Control · doi:10.1177/107327480401100214 · Cited by 26
Reconstitution of hTERT restores tumorigenicity in melanoma-derived c-Myc low-expressing clones
Biroccio, A., Amodei, S., Benassi, B., Scarsella, M., Cianciulli, A. M., Mottolese, M., Bufalo, D. D., Leonetti, C., & Zupi, G. (2002) · Oncogene · doi:10.1038/sj.onc.1205415 · Cited by 27
“Moreover, p53 de®ciency cooperates with telomere dysfunction to accelerate carcinogenesis (Chin et al., 1999).”
BackgroundRas-Induced miR-146a and 193a Target Jmjd6 to Regulate Melanoma Progression
Anelli, V., Ordas, A., Kneitz, S., Muñoz‐Sagredo, L., Gourain, V., Schartl, M., Meijer, A. H., & Mione, M. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00675 · Cited by 26
Velicescu, M., Yu, J., Herbert, B., Shay, J. W., Granada, E., & Dubeau, L. (2003) · PubMed · Cited by 26
Telomere and telomerase in the initial stage of immortalization of esophageal epithelial cell
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Telomerase Activity in Periampullary Tumors Correlates With Aggressive Malignancy
Balcom, J. H., Keck, T., Warshaw, A. L., Antoniu, B. A., Graeme‐Cook, F., & Castillo, C. F. F.-D. (2001) · Annals of Surgery · doi:10.1097/00000658-200109000-00008 · Cited by 26
Molecular mechanisms ofH. pyloriassociated gastric carcinogenesis
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Güneş, Ç., Avila, A. I., & Rudolph, K. L. (2017) · Differentiation · doi:10.1016/j.diff.2017.12.004 · Cited by 29
Xu, J., Chang, W. S., Tsai, C. W., Bau, D., Xu, Y., Davis, J. W., Thompson, T. C., Logothetis, C. J., & Gu, J. H. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.102616 · Cited by 25
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Telomere shortening occurs early during gastrocarcinogenesis
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“At the molecular level, the stepwise progression from an early dysplastic lesion to a malignant tumor is associated with increases in chromosomal instability (CIN), loss of p53 checkpoint function, and telomere shortening [ 6 ].”
BackgroundTelomere Length Modulation in Human Astroglial Brain Tumors
Torre, D. L., Conti, A., Aguennouz, M., Pasquale, M. G. D., Romeo, S., Angileri, F. F., Cardali, S. M., Tomasello, C., Alafaci, C., & Germanò, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0064296 · Cited by 25
“[4,30–32] In the absence of genome checkpoint functions, telomere dysfunction caused by telomere shortening accelerates genomic instability, facilitating cancer initiation and progression.”
BackgroundJeon, H., Choi, Y. Y., Choi, J. E., Lee, W. K., Lee, E., Yoo, S. S., Lee, S. Y., Lee, J., Ick, S., Kim, C. H., et al. (2012) · Molecular Carcinogenesis · doi:10.1002/mc.21972 · Cited by 25
Self-citationTelomerase and Pluripotency Factors Jointly Regulate Stemness in Pancreatic Cancer Stem Cells
Walter, K., Rodríguez-Aznar, E., Ferreira, M. S. V., Frappart, P., Dittrich, T., Tiwary, K., Meessen, S., Lerma, L., Daiß, N., Schulte, L.-A., et al. (2021) · Cancers · doi:10.3390/cancers13133145 · Cited by 24
“The subsequent p53-dependent induction of cell cycle arrest, senescence, apoptosis and the suppression of pluripotency and self-renewal in ESCs as a result of DNA damage has also been demonstrated [42].”
Deficiency of Colonic Telomerase in Ulcerative Colitis
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“The precise effects of telomerase deficiency in terms of promotion or suppression of malignant transformation are, therefore, likely to depend on many factors, including genetic abnormalities that may be present at the same time (24, 25).”
Shammas, M. A., Liu, X., Gavory, G., Raney, K. D., Balasubramanian, S., & Reis, R. J. S. (2004) · Experimental Cell Research · doi:10.1016/j.yexcr.2004.01.003 · Cited by 25
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Telomerase‐independent cell survival in Arabidopsis thaliana
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53BP1 deficiency combined with telomere dysfunction activates ATR-dependent DNA damage response
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“…chromosome ends from degradation and repair activities and, therefore, are essential to ensure chromosome stability (van Steensel et al., 1998; Chin et al., 1999; Karlseder et al., 1999; d’Adda di Fagagna et al., 2003; Takai et al., 2003; Celli and de Lange, 2005; de Lange, 2005; Blasco,…”
Genome stability of programmed stem cell products
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Loss of p16Ink4a Function Rescues Cellular Senescence Induced by Telomere Dysfunction
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“either prevent or promote tumorigenesis [7–9].”
Telomere, DNA damage, and oxidative stress in stem cell aging
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Guilty as CHARGED: p53's expanding role in disease
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“A direct role for p53 in triggering phenotypes upon telomere erosion is indicated by studies in telomerasedeficient mice, where germ cell depletion is partially rescued by p53 loss.(69) While telomere attrition clearly induces DNA damage, thereby activating p53, some effects may also be through ribosome biogenesis def…”
BackgroundThe telomere length landscape of prostate cancer
Livingstone, J. M., Shiah, Y.-J., Yamaguchi, T. N., Heisler, L. E., Huang, V., Lesurf, R., Gebo, T., Carlin, B., Eng, S. E., Drysdale, E., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27223-6 · Cited by 24
GABP couples oncogene signaling to telomere regulation in TERT promoter mutant cancer
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“Telomere dysfunction is associated with chromosomal instability, genome reduplication, chromothripsis, and subsequent focal amplifications or deletions (Chin et al., 1999; Davoli et al., 2010; Saretzki et al., 1999).”
Stem cells, DNA damage, ageing and cancer
Pazhanisamy, S. K. (2009) · Hematology/Oncology and Stem Cell Therapy · doi:10.1016/s1658-3876(09)50005-2 · Cited by 24
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Telomerase and oligodendrocyte differentiation
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Telomeres: Dysfunction, Maintenance, Aging and Cancer
Liao, P., Yan, B., Wang, C., & Lei, P. (2023) · Aging and Disease · doi:10.14336/ad.2023.1128 · Cited by 22
“The complex involvement of telomeres in tumorigenesis was shown by these mouse models, particularly how dysfunctional telomeres promote tumorigenesis while preventing complete malignant transformation [123,137].”
Telomerase recruitment to telomeres
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“The above evidence contributes to a body of previous work demonstrating that short telomeres may more effectively induce a telomeric DDR-like response (Chin et al., 1999; Tsukamoto et al., 2001; d’Adda di Fagagna et al., 2003; IJpma and Greider, 2003; von Zglinicki et al., 2005).”
Change of season-specific telomere lengths in Ginkgo biloba L.
Song, H., Liu, D., Chen, X., Ying, Z., Zhang, B., Li, F., & Lu, H. (2009) · Molecular Biology Reports · doi:10.1007/s11033-009-9627-y · Cited by 22
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“, 1997) and activation of the DNA damage response pathway, leading to tumor suppression as a result of increased cellular apoptosis and senescence (Chin et al., 1999; Gonzalez-Suarez et al., 2000; Farazi et al., 2003; Cosme-Blanco et al., 2007).”
Bocchetta, M., & Carbone, M. (2004) · Oncogene · doi:10.1038/sj.onc.1207855 · Cited by 23
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Function, replication and structure of the mammalian telomere
Broccoli, D. (2004) · Cytotechnology · doi:10.1007/s10616-004-5120-6 · Cited by 22
hTERT promoter polymorphism, -1327C>T, is associated with the risk of epithelial cancer
Iizuka, T., Sawabe, M., Takubo, K., Liu, M., Homma, Y., Suzuki, M., & Arai, T. (2013) · SpringerPlus · doi:10.1186/2193-1801-2-249 · Cited by 21
Telomere biology in aging and cancer: early history and perspectives
Hayashi, M. (2017) · Genes & Genetic Systems · doi:10.1266/ggs.17-00010 · Cited by 23
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Stout, G. J., & Blasco, M. A. (2009) · Disease Models & Mechanisms · doi:10.1242/dmm.002121 · Cited by 22
“…reported previously that a p53-dependent checkpoint is activated in response to critically short telomeres and results in cell death and/or inhibition of proliferation (Chin et al., 1999; Artandi et al., 2000; d’Adda di Fagagna et al., 2004; Rajaraman et al., 2007; Sharpless and DePinho, 2007).”
Maida, Y., Kyo, S., Forsyth, N., Takakura, M., Sakaguchi, J., Mizumoto, Y., Hashimoto, M., Nakamura, M., Nakao, S., & Inoue, M. (2006) · The Journal of Pathology · doi:10.1002/path.2038 · Cited by 21
“Such findings are consistent with those of studies of mTERC −/− p53 −/− double-knockout mice [10], whose cells exhibit”
Sod2 haploinsufficiency does not accelerate aging of telomere dysfunctional mice
Guachalla, L. M., Ju, Z., Koziel, R., von Figura, G., Song, Z., Fusser, M., Epe, B., Jansen-Dűrr, P., & Rudolph, K. L. (2009) · Aging · doi:10.18632/aging.100030 · Cited by 21
Hahn, W. C. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.09.007 · Cited by 21
Telomerase inhibition impairs tumor growth in glioblastoma xenografts
Falchetti, M. L., Fiorenzo, P., Mongiardi, M. P., Petrucci, G., Montano, N., Maira, G., Pierconti, F., Larocca, L. M., Levi, A., & D, R. P. M. (2006) · Neurological Research · doi:10.1179/016164106x116818 · Cited by 21
Guarente, L. (1999) · Nature · doi:10.1038/46185 · Cited by 21
Telomeres: has cancer's Achilles' heel been exposed?
Zumstein, L. A., & Lundblad, V. (1999) · Nature Medicine · doi:10.1038/13451 · Cited by 21
“This p53-independence dispelled previous concerns that telomerase therapy might only be effective in p53-positive tumors, a view that was based on the p53-dependence of apoptosis resulting from loss of telomerase in mic”
Telomeres and telomerase: at the end, it all comes together
Evans, S. K., Bertuch, A. A., & Lundblad, V. (1999) · Trends in Cell Biology · doi:10.1016/s0962-8924(99)01596-2 · Cited by 21
Telomeres and aging: on and off the planet!
Mason, C. E., Sierra, M. A., Feng, H. J., & Bailey, S. M. (2024) · Biogerontology · doi:10.1007/s10522-024-10098-7 · Cited by 23
“In cells with defective checkpoint machinery (including most cancer cells), DDRs that mis-repair dysfunctional telomeres and/or broken DNA ends can result in telomere fusions, chromosome rear-rangements, and rampant genome instability, known drivers of tumorigenesis (Chin et al. 1999).”
Background
Metadata
- Authors
- Chin, L., Artandi, S. E., Shen, Q., Tam, A., Lee, S.-L., Gottlieb, G. J., Greider, C. W., & DePinho, R. A.
- Affiliations
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- Quest Diagnostics (United States) (US)
- Johns Hopkins University (US)
- Corresponding author
- DePinho, Ronald A
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 1999-05
- Volume
- 97
- Issue
- 4
- Pages
- 527-538
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2027779909
- Cited by
- 979
- References
- 44
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 18 · 2023: 21 · 2022: 15 · 2021: 22 · 2020: 15 · 2019: 26 · 2018: 24 · 2017: 23 · 2016: 32 · 2015: 34 · 2014: 23 · 2013: 40 · 2012: 51
- FWCI
- 36.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01hd028317-05, 5r01hd034880-04, 5k08ar002104-04)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K08AR02104-01)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD34880, R01 HD28317)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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, telomere dysfunction, telomere shortening, telomerase deficiency, telomere crisis, carcinogenesis, genomic instability, tumor suppression, apoptosis, growth arrest, telomere length
- MeSH terms
- Animals, Male, Mice, Inbred C57BL, Neoplasms, Phenotype, Spermatozoa, Testis, Tumor Suppressor Protein p53, Telomere, Apoptosis, Telomerase, Mice
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