Role of the TRF2 Telomeric Protein in Cancer and Aging

Muñoz, Purificacı́on; Blanco, Raquel; Blasco, María A.

doi:10.4161/cc.5.7.2636

Cited by 62 publications

(60 citation statements)

References 18 publications

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“…In particular, telomere binding factors (TRF1 and TRF2) attract more and more attention as key regulators of the senescence program in cancer and aging [26]. Therefore, we aimed to determine whether TRF2 might serve as a substrate for uPAR-related ubiquitination and proteasomal degradation and thus may trigger doxorubicin-induced, uPAR-controlled senescence in VSMC.…”

Section: Resultsmentioning

confidence: 99%

Urokinase Receptor Mediates Doxorubicin-Induced Vascular Smooth Muscle Cell Senescence via Proteasomal Degradation of TRF2

et al. 2012

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The anthracycline doxorubicin is a widely used effective anti-cancer drug. However, its application and dosage are severely limited due to its cardiotoxicity. The exact mechanisms of doxorubicin-induced cardiotoxic side effects remain poorly understood. Even less is known about the impact of doxorubicin treatment on vascular damage. We found that low doses of doxorubicin induced a senescent response in human primary vascular smooth muscle cells (VSMC). We observed that expression of urokinase receptor (uPAR) was upregulated in response to doxorubicin. Furthermore, the level of uPAR expression played a decisive role in developing doxorubicin-induced senescence. uPAR silencing in human VSMC by means of RNA interference as well as uPAR knockout in mouse VSMC resulted in abrogation of doxorubicin-induced cellular senescence. On the contrary, uPAR overexpression promoted VSMC senescence. We further found that proteasomal degradation of telomeric repeat binding factor 2 (TRF2) mediates doxorubicin-induced VSMC senescence. Our results demonstrate that uPAR controls the ubiquitin-proteasome system in VSMC and regulates doxorubicin-induced TRF2 ubiquitination and proteasomal degradation via this mechanism. Therefore, VSMC senescence induced by low doses of doxorubicin may contribute to vascular damage upon doxorubicin treatment. uPAR-mediated TRF2 ubiquitination and proteasomal degradation are further identified as a molecular mechanism underlying this process.

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Section: Resultsmentioning

confidence: 99%

Urokinase Receptor Mediates Doxorubicin-Induced Vascular Smooth Muscle Cell Senescence via Proteasomal Degradation of TRF2

et al. 2012

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“…Depletion of endogenous TRF2 levels either by overexpression of dominant negative TRF2 (TRF2-DN) or through genetic knockout approaches in mouse cells with long telomeres results in massive chromosomal fusions with telomeric sequence at the sites of fusions. Mouse models in which shelterin components have been deleted experience telomere dysfunction, a DDR and chromosomal fusions resembling those observed in telomerase null mice 79,81,[84][85][86][87][88] . These results suggest that both critically short telomeres and direct disruption of the shelterin structure can initiate telomere dysfunction, trigger a DDR and chromosomal fusions.…”

Section: Box 1 the Shelterin Complexmentioning

confidence: 99%

Telomere dysfunction and tumour suppression: the senescence connection

2008

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Long lived organisms such as humans have evolved several intrinsic tumor suppressor mechanisms to combat the slew of oncogenic somatic mutations that constantly arise in proliferating stem cell compartments. One of these anti-cancer barriers is the telomere, a specialized nucleoprotein that caps the ends of eukaryotic chromosome. Impaired telomere function activates the canonical DNA damage response pathway that engages p53 to initiate apoptosis or replicative senescence. Here, we discuss how p53-dependent senescence induced by dysfunctional telomeres may be as potent as apoptosis in suppressing tumorigenesis in vivo.More than 40 years ago, Hayflick and Moorhead discovered that normal human diploid fibroblasts (HDFs) cannot grow indefinitely in culture 1 . Rather, their proliferative capacities are intrinsically limited. After 60-80 population doublings in culture, HDFs stop dividing and adopt a phenotype characterized by large, flat cell size, a vacuolated morphology, inability to synthesize DNA, and the presence of the senescence-associated β-galactosidase (SA-β-gal) marker 2 . We now know that the endpoint of this proliferative limit, termed replicative senescence, is due largely to erosion of telomeres, protective structures that cap the end of all eukaryotic chromosomes. Confirmation of this came from studies in which telomerase, the enzyme that maintains telomeres, was ectopically expressed in normal human somatic cells 3,4 . Activation of telomerase results in telomere elongation, abrogation of replicative senescence, a normal karyotype and cellular immortalization. These results clearly demonstrate that telomere length determines the proliferative lifespan of HDFs, and that upregulation of telomerase activity (hence telomere length) restores proliferative capacity.A large body of experimental evidence has demonstrated that telomere attrition contributes to tumorigenesis by promoting genome instability 5 . However, in the setting of a competent p53 pathway, mouse models have recently shown that telomere shortening is also tumor suppressive by promoting replicative senescence to inhibit tumor formation. In this Perspective, we will discuss how telomeres shorten with cell replication and how this might initiate a DNA damage response to induce replicative senescence (and cell death) and ultimately prevent tumorigenesis.

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“…In agreement with the short telomeres in these mice, a model has been proposed in which increased TRF2 expression results in higher XPF-ERCC1 activity at telomeres, leading to rapid XPF-dependent telomere degradation (Muñoz et al, 2005;Wu et al, 2007) and to the early onset of skinaging phenotypes (Muñoz et al, 2005). Concomitantly, decreased XPF activity at UV-induced lesions might lead to increased DNA damage and skin cancer (Muñoz et al, 2005;Muñoz et al, 2006; Blanco et al, 2007). Remarkably, in the absence of telomerase activity, telomere shortening is accelerated further in K5TRF2 mice and UV-induced carcinogenesis is also increased (Blanco et al, 2007), indicating that the skin phenotypes associated with increased TRF2 expression are provoked by the presence of critically short telomeres and increased DNA damage in these mice.…”

Section: Introductionmentioning

confidence: 79%

“…TRF2 has been found to be upregulated in human cancers, including in SCC and BCC in the skin (Hsu et al, 2005;Oh et al, 2005;Muñoz et al, 2005). In this regard, mice with increased TRF2 expression show critically short telomeres, increased telomere damage and an increased incidence of cancer (Muñoz et al, 2005), suggesting that deregulated TRF2 expression might favor a pro-tumorigenic phenotype (Muñoz et al, 2006). Here, we describe the impact of increased TRF2 levels on ESC behavior and, using mouse genetics, we further dissect the pathways involved in this process.…”

Section: Discussionmentioning

confidence: 99%

Genetic dissection of the mechanisms underlying telomere-associated diseases: impact of the TRF2 telomeric protein on mouse epidermal stem cells

Stout

Blasco

2009

Disease Models &Amp; Mechanisms

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SUMMARYTRF2 is a telomere-binding protein involved in the protection of chromosome ends. Interestingly, TRF2 is overexpressed in a number of human cancers. Mice with increased TRF2 expression (K5TRF2 mice) display a severe skin phenotype including an increase in skin cancer and premature skin degeneration, which includes increased skin hyperpigmentation and skin dryness; these pathologies are concomitant with dramatic telomere shortening and increased chromosomal instability. Here, we show that K5TRF2 mice have a severe epidermal stem cell (ESC) dysfunction, which is reversed by abrogation of p53 in the absence of rescue of telomere length. Importantly, p53 deletion also rescues severe skin hyperpigmentation in these mice through regulation of alpha-melanocyte-stimulating hormone (α-MSH). In addition, skin carcinogenesis is accelerated in K5TRF2/p53 -/-mice owing to attenuated p21 induction, which enables cell proliferation to resume. Altogether, these results reveal the existence of a DNA damagedependent checkpoint that acts on ESCs with critically short telomeres and restricts skin proliferation, thereby increasing protection against skin cancer; however, the checkpoint also leads to premature skin aging phenotypes. Finally, the results described here are relevant to our understanding of the pathobiology of those human diseases that are characterized by the presence of critically short telomeres (hereafter referred to as 'telopathies'), such as dyskeratosis congenita which causes severe skin phenotypes including skin hyperpigmentation and skin cancer.

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Role of the TRF2 Telomeric Protein in Cancer and Aging

Cited by 62 publications

References 18 publications

Urokinase Receptor Mediates Doxorubicin-Induced Vascular Smooth Muscle Cell Senescence via Proteasomal Degradation of TRF2

Urokinase Receptor Mediates Doxorubicin-Induced Vascular Smooth Muscle Cell Senescence via Proteasomal Degradation of TRF2

Telomere dysfunction and tumour suppression: the senescence connection

Genetic dissection of the mechanisms underlying telomere-associated diseases: impact of the TRF2 telomeric protein on mouse epidermal stem cells

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