The cellular level of telomere dysfunction determines induction of senescence or apoptosis<i>in vivo</i>

Lechel, André; Satyanarayana, A.; Ju, Zhenyu; Plentz, Ruben R.; Schaetzlein, Sonja; Rudolph, Cornelia; Wilkens, Ludwig; Wiemann, Stefanie U.; Saretzki, Gabriele; Malek, Nisar P.; Manns, Michael P.; Buer, Jan; Rudolph, K. Lenhard

doi:10.1038/sj.embor.7400352

Cited by 90 publications

(78 citation statements)

References 24 publications

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“…The expression of these alleles was followed by Western blot (Figure 1b (Figure 2a). Such a growth phenotype was already observed in a similar cellular setting or when telomere dysfunction is induced in mouse liver (Lechel et al, 2005). Immunofluorescence studies of the number of cells expressing the Myc-tagged TRF2 protein show that the percentage of M-TRF2 DBDM -positive cells does not decrease when the cells regain their full growth capacity ( Supplementary Figure 1), suggesting a progressive selection of cells poorly expressing the transgene.…”

Section: Induction Of Different Types Of Trf2 Dysfunction In Telomerisupporting

confidence: 56%

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

et al. 2005

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Although telomere instability is observed in human tumors and is associated with the development of cancers in mice, it has yet to be established that it can contribute to the malignant transformation of human cells. We show here that in checkpoint-compromised telomerase-positive human fibroblasts an episode of TRF2 inhibition promotes heritable changes that increase the ability to grow in soft agar, but not tumor growth in nude mice. This transforming activity is associated to a burst of telomere instability but is independent of an altered control of telomere length. Moreover, it cannot be recapitulated by an increase in chromosome breaks induced by an exposure to cradiations. Since it can be revealed in the context of telomerase-proficient human cells, telomere dysfunction might contribute to cancer progression even at late stages of the oncogenesis process, after the telomerase reactivation step.

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Section: Induction Of Different Types Of Trf2 Dysfunction In Telomerisupporting

confidence: 56%

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

et al. 2005

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“…TRF2 is essential for telomere capping, and inhibition of TRF2 induces hallmark features of telomere dysfunction that also occur in response to telomere shortening (14,20). The molecular pathways of chromosomal fusion formation show differences when telomere dysfunction is induced by telomere shortening or TRF2 inhibition (21).…”

Section: Resultsmentioning

confidence: 99%

Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis

Begus‐Nahrmann¹,

Hartmann²,

Kraus³

et al. 2012

J. Clin. Invest.

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Telomere shortening limits the proliferative capacity of a cell, but perhaps surprisingly, shortening is also known to be associated with increased rates of tumor initiation. A current hypothesis suggests that telomere dysfunction increases tumor initiation by induction of chromosomal instability, but that initiated tumors need to reactivate telomerase for genome stabilization and tumor progression. This concept has not been tested in vivo, since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis in a mouse model of inducible telomere dysfunction on a telomerase-proficient background, in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc -/-), and in WT mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell-cycle arrest, and apoptosis in telomerase-deficient liver tumors. Together, these data provide in vivo evidence that transient telomere dysfunction during early or late stages of tumorigenesis promotes chromosomal instability and carcinogenesis in telomerase-proficient mice.

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“…12 In liver cells, the level of telomere dysfunction appears to determine whether p53-dependent or p53-independent responses are induced. 39 The Hep3B and Huh7 cell lines used in this study are p53-mutant, 40 yet show relatively rapid and strong inhibition of tumor growth in response to telomerase inhibition. These data, together with other reports, suggest that p53 might not be a strong modulator in telomere dysfunction-induced responses affecting the viability of the hepatoma cells.…”

Section: Discussionmentioning

confidence: 99%

Telomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma

et al. 2005

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Most cancer cells have an immortal growth capacity as a consequence of telomerase reactivation. Inhibition of this enzyme leads to increased telomere dysfunction, which limits the proliferative capacity of tumor cells; thus, telomerase inhibition represents a potentially safe and universal target for cancer treatment. We evaluated the potential of two thio-phosphoramidate oligonucleotide inhibitors of telomerase, GRN163 and GRN163L, as drug candidates for the treatment of human hepatoma. GRN163 and GRN163L were tested in preclinical studies using systemic administration to treat flank xenografts of different human hepatoma cell lines (Hep3B and Huh7) in nude mice. The studies showed that both GRN163 and GRN163L inhibited telomerase activity and tumor cell growth in a dose-dependent manner in vitro and in vivo. The potency and efficacy of the lipid-conjugated antagonist, GRN163L, was superior to the nonlipidated parent compound, GRN163. Impaired tumor growth in vivo was associated with critical telomere shortening, induction of telomere dysfunction, reduced rate of cell proliferation, and increased apoptosis in the treatment groups. In vitro, GRN163L administration led to higher prevalence of chromosomal telomere-free ends and DNA damage foci in both hepatoma cell lines. In addition, in vitro chemosensitivity assay showed that pretreatment with GRN163L increased doxorubicin sensitivity of Hep3B. In conclusion, our data support the development of GRN163L, a novel lipidated conjugate of the telomerase inhibitor GRN163, for systemic treatment of human hepatoma. In addition to limiting the proliferative capacity of hepatoma, GRN163L might also increase the sensitivity of this tumor type to conventional chemotherapy. Similar to other malignant human tumor types, 4 over 80% of human HCC biopsies show activation of telomerase. 5 In contrast, most somatic human tissues, including normal liver, 6 show no or very low levels of telomerase activity. The main function of telomerase is the de novo synthesis of telomeres, which cap the chromosome ends of eukaryotic cells and protect chromosome ends from fusion and DNA damage recognition. 7 Because of the "end replication problem" of DNA polymerase, telomeres shorten during each cell division by 50 to 100 bp. 8 Telomere shortening to a critical length and/or the uncapping of the telomere limit the growth of primary human cells to a finite number of cell divisions, leading to either replicative senescence or crisis. 9-11 A critically short telomere

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The cellular level of telomere dysfunction determines induction of senescence or apoptosisin vivo

Cited by 90 publications

References 24 publications

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis

Telomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma

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