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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.
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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 · 21 Not checked yet · 6 Own method · 4 No basis given · 1 Check pending
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“Correspondingly, the loss of telomere function and p53 deficiency cooperated to initiate the transformation process.”
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“Coincident with severe telomere shortening and associated genomic instability, p53 is activated, leading to growth arrest and/or apoptosis.”
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“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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“We found that p53 mediates the adverse effects of critically shortened telomeres.”
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“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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“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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“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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“Furthermore, loss of telomere function and p53 deficiency can cooperate to enhance transformation.”
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“Deletion of p53 significantly attenuated the adverse cellular and organismal effects of telomere dysfunction, but only during the earliest stages of genetic crisis.”
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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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“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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“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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“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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“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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“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”
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- Not checked yetcites Lee et al. 1998 source
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“Significantly, loss of p53 rescues the cell cycle arrest in MEFs and the apoptotic elimination of male germ cells.”
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“loss of p53 abrogated this block.”
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“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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“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 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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“Similar differences were observed in low-density seeding experiments (data not shown).”
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“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”
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- Not checked yetcites Hayflick and Moorhead 1961 source
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“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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“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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“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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“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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“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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“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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“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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“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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“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.”
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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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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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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).”
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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.”
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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
“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.
- Checkable: passes — It can be checked against evidence.
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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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It may state two separate claims as one.
- 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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Probably not a substantial claim. It may state two separate claims as one.
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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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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 measuredIn 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
“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]
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]
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]
Citations
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Self-citation
Cited by
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Items 801–900 of 975
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Telomeres and Telomerase in Aging, Regeneration and Cancer
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Murine Models of Dysfunctional Telomeres and Telomerase
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Chicurel, M. (2001) · Science of Aging Knowledge Environment · doi:10.1126/sageke.2001.1.oa3 · Cited by 3
Mehdipour, P. (2012) · Springer eBooks · doi:10.1007/978-94-007-4632-9_5 · Cited by 2
Cell Cycle Control in Pancreatic Cancer Pathogenesis
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“In experimental models, depletion of telomerase results in telomere shortening, limiting self renewal capacity of stem cells, exhaustion of the stem cell pool and finally promoting premature aging whereas dysfunctional telomeres can cause age-related pathologies, depending on the functionality of the DNA-repair machin…”
BackgroundTelomere dysfunction suppresses multiple endocrine neoplasia in mice
Lee, J., Anver, M. R., Kost‐Alimova, M., Protopopov, A. I., DePinho, R. A., & Rane, S. G. (2014) · Genes & Cancer · doi:10.18632/genesandcancer.31 · Cited by 2
“Telomerase deficiency in combination with mutations in distinct tumor suppressor genes, except p53, significantly diminishes tumorigenesis potential [36-40] suggesting that telomerase inhibitors may be effective as anti-cancer agents [41-43].”
InfluentialSelf-citationClonal cell populations unresponsive to radiosensitization induced by telomerase inhibition
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Failing to adapt – the ageing immune system's role in cancer pathogenesis
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Critical role of the POT1 OB domain in maintaining genomic stability
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Indirect but just as effective
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Telomeres and Telomerase: Distinctive Roles in Liver Regeneration, Cirrhosis and Carcinogenesis
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“The other outcome of critical telomere shortening and activation of the p53 pathway is the induction of apoptosis [15, 33].”
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Telomere Binding Proteins and Disease
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Telomerase, DNA damage and apoptosis
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Telomerase as a potential anticancer target: growth inhibition and genomic instability
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“Mice lacking telomerase have active p53[15].”
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“30,31 We detected telomere shortening 7 days after TERT knockdown in MV-4-11 but not MOLM-13 cells (Figure 2K).”
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“Since telomere dysfunction induces DNA damage that activates p53 ( 36 ), we hypothesize that DMTF1 down-regulation may be indirectly attributed to p53 induction since DMTF1 is not a known p53 target gene ( 37 ). p53 depletion rescued DMTF1 protein expression in TERT-deficient hNPC (fig.”
Hernández-Silva, D., Matabuena, M., Guío-Carrión, A., Aguilera, J. M., Martín, A., Megias, D., Mínguez, D., Demessant-Flavigny, A. L., Castillejo, I., Bernerd, F., et al. (2026) · Journal of Photochemistry and Photobiology B Biology · doi:10.1016/j.jphotobiol.2026.113375 · Cited by 1
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Telomeres and Lifestyle Choices
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“Shorter telomeres can also induce genomic instability [Chin et al., 1999; De Lange et al., 2005] by mediating chromosome end-to-end fusions and may contribute to telomere stabilization and development of cancer [Chin et al.”
BackgroundInfluentialOrganelle Stress and mTOR in Aging-Associated Inflammation
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Cancer, Senescence, and Aging: Translation from Basic Research to Clinics
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Self-citationAge and Disease Related Telomere Manifestations - A Review
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“of cells, apoptosis and senescence in stem and progenitor cells [13-16].”
BackgroundMolecular Mechanisms of Cardiovascular Aging
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“central executor of the DNA damage response pathway.(76)”
Mind-Body Wellness Program Benefits
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Telomere Shortening and Telomerase Activation during Cancer Formation
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“There is evidence that loss of checkpoint function can accelerate tumor formation in response to telomere dysfunction, specifically the loss of p53 checkpoint function (Chin et al. 1999).”
BackgroundGenetic Susceptibility and High Risk Groups for Pancreatic Cancer
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Hypoxic Regulation of Telomerase Gene Expression in Cancer
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Effects of Coenzyme Q10 on H2O2-Induced Oxidative Stress of Human Keratinocytes
Suntornnont, N., Kovavisarach, A., & Tammachote, R. (2025) · OBM Genetics · doi:10.21926/obm.genet.2501279 · Cited by 1
MECHANISMS LEADING TO CHROMOSOMAL INSTABILITY IN ORAL CANCER CELLS
Reshmi, S. C. (2005) · D-Scholarship@Pitt (University of Pittsburgh) · Cited by 1
Lessons on p53 from Mouse Models
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Genetische Grundlagen der Kanzerogenese
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Mouse Model: Telomeres and Telomerase in Stem Cell and Cancer
Huang, X., & Ju, Z. (2009) · Humana Press eBooks · doi:10.1007/978-1-60327-879-9_6 · Cited by 1
“The in vivo consequences of p53 deletion did not rescue the survival of telomere dysfunctional mice due to the early onset of tumors, which did not allow ageing study in this mouse model ( 11 ).”
InfluentialSenescence, Apoptosis, and Cancer
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Cellular Senescence Pathways in Mouse and Human
Wadhwa, R., Hasan, M. K., & Kaul, S. C. (2003) · Springer eBooks · doi:10.1007/978-94-017-0669-8_12 · Cited by 1
IL-7R{alpha} deficiency in p53null mice exacerbates thymocyte telomere erosion and lymphomagenesis
Cui, Y. R., Kibe, R., Zhang, S., Guo, D., Marrero, L., Tsien, F., Rodrı́guez, P. C., Zieske, A. W., Huang, J., Li, W., et al. (2012) · The Journal of Immunology · Cited by 1
Regulation of the Liver Cell Mass
Malek, N. P., Rudolph, K. L., & Diehl, A. M. (2007) · Wiley eBooks · doi:10.1002/9780470691861.ch2e · Cited by 1
Papillomavirus infection and telomerase activation
Allen, H. K., & Klingelhutz, A. J. (2003) · Papillomavirus Report · doi:10.1179/095741903225001598 · Cited by 1
The p53 Pathway, Cancer and Aging
Braithwaite, A. W., & Edwards, S. J. (2003) · Springer eBooks · doi:10.1007/978-94-017-0669-8_8 · Cited by 1
Wang, J. (2011) · OPen Access Repositorium der Universität Ulm (OPARU) (Ulm University) · doi:10.18725/oparu-1953 · Cited by 1
Hahn, W. C. (2003) · Cancer Research and Treatment · doi:10.4143/crt.2003.35.6.467 · Cited by 1
Programmed Death Phenomena at Various Levels of Development of the Living Systems
Skulachev, V. P. (2003) · Springer eBooks · doi:10.1007/978-94-010-0064-2_5 · Cited by 1
Telomerase Activity in Human Umbilical Cord Cell Populations Containing Hematopoietic Stem Cells
Murthy, V. (2002) · Digital WPI · Cited by 1
A feedback-loop between telomerase activity and stemness factors regulates PDAC stem cellsPreprint
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. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.11.02.361931 · Cited by 1
“(37) Thus, a tightly coordinated regulation of stemness-associated transcription factors 447 and pathways is essential for the preservation of “stemness”.”
The Telomere Length Landscape of Prostate CancerPreprint
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) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.05.22.445239 · Cited by 1
Genetische Grundlagen der Kanzerogenese
Bartram, C. R. (2004) · Springer eBooks · doi:10.1007/978-3-662-06670-6_4 · Cited by 1
Clapp, D. W., & Nalepa, G. (2014) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.718311742.793492304 · Cited by 1
cGAS-STING is responsible for aging of telomerase deficient zebrafishPreprint
Şerifoğlu, N., Allavena, G., Lopes-Bastos, B., Marzullo, M., Bousounis, P., Trompouki, E., & Ferreira, M. G. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.11.584360 · Cited by 1
Genomic DNA Copy Number Alterations in Mouse Cancer Models and Human Cancer
Albertson, D. G. (2011) · Springer eBooks · doi:10.1007/978-0-387-69805-2_8
The DNA damage response pathway in oral squamous cell carcinoma
Parikh, R. A. (2006) · D-Scholarship@Pitt (University of Pittsburgh)
Replicative Senescence as an Intrinsic Tumor-Suppressor Mechanism
Chang, S. S. (2009) · Springer eBooks · doi:10.1007/978-1-4419-1075-2_8
Animal Models for Mechanistic Cancer Research
Wang, Z. (2003) · Handbook of experimental pharmacology · doi:10.1007/978-3-662-08602-5_15
Maintenance of Telomeres in Cancer
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Primary Hepatocellular Carcinoma
Dufour, J., & Hora, C. (2010) · Molecular pathology library · doi:10.1007/978-1-4419-7107-4_56
Control of Telomeric DNA Replication: Genetics, Molecular Biology, and Physiology
Matsuura, A., & Matsui, A. (2011) · InTech eBooks · doi:10.5772/18551
“In cells in which p53 is mutated, dysfunctional telomeres promote genome instability and progression to cancer, indicating that replicative senescence contributes to the suppression of tumorigenesis (Chin et al., 1999).”
Telomeres and Aging, Cancer, and Hepatic Fibrosis
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Genetic Requirements for the Transformation of Human Cells
Seger, Y. R. (2002) · doi:10.21236/ada410207
Transcriptional Regulation of Human Telomerase
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Cell-cycle control by protein kinase B
Kops, G. J. P. L. (2001) · Utrecht University Repository (Utrecht University)
DNA Damage, Checkpoint Responses, and Cell Cycle Control in Aging Stem Cells
Sperka, T., Nalapareddy, K., & Rudolph, K. L. (2010) · Else Kröner-Fresenius Symposia · doi:10.1159/000312653
Whitaker, H. (2002) · Enlighten: Theses (The University of Glasgow)
Mehdipour, P., & Parsa, N. (2012) · Springer eBooks · doi:10.1007/978-94-007-4632-9_7
Werner Syndrome, Telomeres, and Stress Signaling: Implications for Future Therapies?
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Mechanisms of DNA Double-Strand Break Repair in Hematopoietic Homeostasis and Oncogenesis
Maas, S. A., Caddle, L. B., & Mills, K. D. (2008) · Springer eBooks · doi:10.1007/978-0-387-69132-9_4
“mice doubly deficient for these genes subsequently show increased rates of genome instability that result in tumorigenesis (Chin et al., 1999).”
BackgroundThe p53-induced Wig-1 protein: Studies of interaction partners and expression in tumor cells
Prahl, M. (2008) · Figshare
Telomerasa: regulación, diana terapéutica y significado clínico en neoplasias humanas
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Cellular stress in vitro and longevity in vivo
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Telomere Dysfunction and Senescence in Stem Cell and Tissues Aging
Nalapareddy, K., & Rudolph, K. L. (2009) · Springer eBooks · doi:10.1007/978-1-4419-1075-2_9
Contributions of Telomerase to Tumorigenesis
Possemato, R., & Hahn, W. C. (2007) · Humana Press eBooks · doi:10.1007/978-1-59745-221-2_9
Structure and Function of the Telomere
Johnson, J. E., & Broccoli, D. (2007) · Humana Press eBooks · doi:10.1007/978-1-59745-221-2_7
“The cellular senescence and apoptosis responsible for this decrease in proliferation are dependent on the action of the tumor-suppressor protein, p53 ( 106 ).”
BackgroundInfluentialTelomere Dysfunction and the DNA Damage Response
Diehl, M. C., Elmore, L. W., & Holt, S. E. (2009) · Humana Press eBooks · doi:10.1007/978-1-60327-879-9_4
Telomeres and Telomerase in Adrenocortical Carcinoma
Else, T., & Hornsby, P. J. (2009) · Springer eBooks · doi:10.1007/978-0-387-77236-3_13
Cancer Associated Testis Antigens
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Identifying cancer-causing noncoding RNAs
le Sage, & Karel, C. (2008) · Leiden Repository (Leiden University)
Telomere dynamics in chronic myeloid leukaemia
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The Influence of Biological Ageing in the Pathogenesis of Colorectal Cancer
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ANGIOSTATIC MECHANISMS OF ENDOGENOUS ANGIOGENESIS INHIBITORS
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Telomerase: Roles in aging, cancer and hereditary disease
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Utilization of Werner syndrome mouse model in studying premature aging and tumor
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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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