TGF-β induces telomerase-dependent pancreatic tumor cell cycle arrest

Cassar, Lucy; Li, He; Jiang, Fuming; Liu, Junping

doi:10.1016/j.mce.2010.02.002

Cited by 20 publications

(17 citation statements)

References 72 publications

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“…Indeed, our results are consistent with findings that the expression of the human telomerase reverse transcriptase (h TERT ) (a key element in telomerase activation, telomere maintenance and tumor development) is mediated by SMAD3 (20,42–44). …”

Section: Discussionsupporting

confidence: 92%

Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans

Mangino

Hwang

Spector

et al. 2012

Human Molecular Genetics

216

243

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Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10−11) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10−8). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10−8) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10−8) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.

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Section: Discussionsupporting

confidence: 92%

Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans

Mangino

Hwang

Spector

et al. 2012

Human Molecular Genetics

216

243

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“…For example, a decrease in expression of c-MYC, TIN2, DKC1, and RFC1 genes which are positive regulators of telomerase, was seen in MST-312 treated brain tumour cells. There was also a decrease in expression of Transforming growth factor beta ( TGFB), a multifunctional cytokine that represses TERT expression via down-regulation on c-myc [ 29 , 30 ]. Even though we observed down-regulation in expression of MYC gene, the level of TERT protein and gene expression was not altered in MST-312 treated brain tumour cells.…”

Section: Resultsmentioning

confidence: 99%

Targeting DNA-PKcs and telomerase in brain tumour cells

et al. 2014

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BackgroundPatients suffering from brain tumours such as glioblastoma and medulloblastoma have poor prognosis with a median survival of less than a year. Identifying alternative molecular targets would enable us to develop different therapeutic strategies for better management of these tumours.MethodsGlioblastoma (MO59K and KNS60) and medulloblastoma cells (ONS76) were used in this study. Telomerase inhibitory effects of MST-312, a chemically modified-derivative of epigallocatechin gallate, in the cells were assessed using telomere repeat amplification protocol. Gene expression analysis following MST-312 treatment was done by microarray. Telomere length was measured by telomere restriction fragments analysis. Effects of MST-312 on DNA integrity were evaluated by single cell gel electrophoresis, immunofluorescence assay and cytogenetic analysis. Phosphorylation status of DNA-PKcs was measured with immunoblotting and effects on cell proliferation were monitored with cell titre glow and trypan blue exclusion following dual inhibition.ResultsMST-312 showed strong binding affinity to DNA and displayed reversible telomerase inhibitory effects in brain tumour cells. In addition to the disruption of telomere length maintenance, MST-312 treatment decreased brain tumour cell viability, induced cell cycle arrest and double strand breaks (DSBs). DNA-PKcs activation was observed in telomerase-inhibited cells presumably as a response to DNA damage. Impaired DNA-PKcs in MO59J cells or in MO59K cells treated with DNA-PKcs inhibitor, NU7026, caused a delay in the repair of DSBs. In contrast, MST-312 did not induce DSBs in telomerase negative osteosarcoma cells (U2OS). Combined inhibition of DNA-PKcs and telomerase resulted in an increase in telomere signal-free chromosomal ends in brain tumour cells as well. Interestingly, continual exposure of brain tumour cells to telomerase inhibitor led to population of cells, which displayed resistance to telomerase inhibition-mediated cell arrest. DNA-PKcs ablation in these cells, however, confers higher cell sensitivity to telomerase inhibition, inducing cell death.ConclusionsEfficient telomerase inhibition was achieved with acute exposure to MST-312 and this resulted in subtle but significant increase in DSBs. Activation of DNA-PKcs might indicate the requirement of NHEJ pathway in the repair telomerase inhibitor induced DNA damage. Therefore, our results suggest a potential strategy in combating brain tumour cells with dual inhibition of telomerase and NHEJ pathway.

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“…Whereas activation of the Ras-ERK pathway stimulates proliferation (49) and inhibits differentiation (52) of AECII, inhibition of the Ras-ERK pathway is essential for TGF-␤1-induced AECII differentiation (52). Interestingly, we and others showed previously that whereas mitogens up-regulate telomerase activity by Ets transcriptional activation of the TERT gene (53,54), TGF-␤ family members down-regulate telomerase activity by Smad3 transcriptional repression of TERT in epithelial cell lines (55)(56)(57). These data together suggest that the EGF-Ets and TGF-␤-Smad3 pathways regulate the TERT gene and proliferative potential of AECII in a reciprocally opposing manner.…”

Section: Volume 290 • Number 52 • December 25 2015mentioning

confidence: 99%

Telomerase Deficiency Causes Alveolar Stem Cell Senescence-associated Low-grade Inflammation in Lungs

Chen

Zhang

Chen

et al. 2015

Journal of Biological Chemistry

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Mutations of human telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT) are associated with a subset of lung aging diseases, but the mechanisms by which TERC and TERT participate in lung diseases remain unclear. In this report, we show that knock-out (KO) of the mouse gene Terc or Tert causes pulmonary alveolar stem cell replicative senescence, epithelial impairment, formation of alveolar sacs, and characteristic inflammatory phenotype. Deficiency in TERC or TERT causes a remarkable elevation in various proinflammatory cytokines, including IL-1, IL-6, CXCL15 (human IL-8 homolog), IL-10, TNF-␣, and monocyte chemotactic protein 1 (chemokine ligand 2 (CCL2)); decrease in TGF-␤1 and TGF␤RI receptor in the lungs; and spillover of IL-6 and CXCL15 into the bronchoalveolar lavage fluids. In addition to increased gene expressions of ␣-smooth muscle actin and collagen 1␣1, suggesting myofibroblast differentiation, TERC deficiency also leads to marked cellular infiltrations of a mononuclear cell population positive for the leukocyte common antigen CD45, low-affinity Fc receptor CD16/CD32, and pattern recognition receptor CD11b in the lungs. Our data demonstrate for the first time that telomerase deficiency triggers alveolar stem cell replicative senescence-associated low-grade inflammation, thereby driving pulmonary premature aging, alveolar sac formation, and fibrotic lesion.

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TGF-β induces telomerase-dependent pancreatic tumor cell cycle arrest

Cited by 20 publications

References 72 publications

Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans

Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans

Targeting DNA-PKcs and telomerase in brain tumour cells

Telomerase Deficiency Causes Alveolar Stem Cell Senescence-associated Low-grade Inflammation in Lungs

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