Telomerase activity is required for bleomycin-induced pulmonary fibrosis in mice

Liu, Tianju; Chung, Myoung Ja; Ullenbruch, Matthew; Yu, Hongfeng; Jin, Hong; Hu, Biao; Choi, Yoon Young; Ishikawa, Fuyuki; Phan, Sem H.

doi:10.1172/jci32369

Cited by 72 publications

(95 citation statements)

References 53 publications

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“…This murine model has been widely used to exploit telomereindependent functions of TERT in G1TERT −/− mice with normal telomere lengths, as well as phenotypes that occur as a result of progressive telomere attrition in third generation G3TERT −/− mice. 18,[34][35][36][37] Conversely, constitutive expression of TERT in transgenic mice does not elongate telomeres 22 because TERT only elongates critically short telomeres. 38,39 Therefore, this transgenic model provides another means to study TERT activities that occur independently of its function to extend telomeres.…”

Section: Discussionmentioning

confidence: 99%

Telomerase Reverse Transcriptase Deficiency Prevents Neointima Formation Through Chromatin Silencing of E2F1 Target Genes

Endorf

Qing

Aono

et al. 2017

ATVB

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Objective-Aberrant proliferation of smooth muscle cells (SMC) in response to injury induces pathological vascular remodeling during atherosclerosis and neointima formation. Telomerase is rate limiting for tissue renewal and cell replication; however, the physiological role of telomerase in vascular diseases remains to be determined. The goal of the present study was to determine whether telomerase reverse transcriptase (TERT) affects proliferative vascular remodeling and to define the molecular mechanism by which TERT supports SMC proliferation. Approach and Results-We first demonstrate high levels of TERT expression in replicating SMC of atherosclerotic and neointimal lesions. Using a model of guidewire-induced arterial injury, we demonstrate decreased neointima formation in TERT-deficient mice. Studies in SMC isolated from TERT-deficient and TERT overexpressing mice with normal telomere length established that TERT is necessary and sufficient for cell proliferation. TERT deficiency did not induce a senescent phenotype but resulted in G1 arrest albeit hyperphosphorylation of the retinoblastoma protein. This proliferative arrest was associated with stable silencing of the E2F1-dependent S-phase gene expression program and not reversed by ectopic overexpression of E2F1. Finally, chromatin immunoprecipitation and accessibility assays revealed that TERT is recruited to E2F1 target sites and promotes chromatin accessibility for E2F1 by facilitating the acquisition of permissive histone modifications. cultured cells, TERT is induced in both activated macrophages and proliferating SMC. 14,17 In SMC, the transient increase in TERT abundance in response to growth factor stimulation serves a mitogenic role because inhibition of TERT by oligonucleotide or pharmacological targeting inhibits SMC proliferation. 15,[17][18][19][20] Furthermore, acute telomerase downregulation using TERT antisense RNA decreases proliferation of SMC isolated from genetically hypertensive rats. 21 Although recent genetic experiments established that the mitogenic activity of TERT requires neither telomere extension nor the catalytic activity, 5-8 the molecular mechanisms by which TERT supports cellular proliferation remain elusive. Conclusions-TheseIn this study, we used a genetic model of TERT deficiency to investigate the transcriptional mechanisms underlying the mitogenic activity of TERT during proliferative vascular remodeling. Our studies reveal that TERT deletion prevents neointima formation and SMC proliferation by inducing a silenced chromatin environment at S phase gene promoters. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Results TERT Is Expressed in Replicating Neointimal Smooth Muscle CellsTERT protein expression was first analyzed in neointimal SMC of human coronary artery atherosclerotic lesions from hearts explanted during cardiac transplantation. Although TERT expression is considered negligible in normal arteries, 13,14 we confirmed abundant TERT expression in the SMCrich neoint...

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Section: Discussionmentioning

confidence: 99%

Telomerase Reverse Transcriptase Deficiency Prevents Neointima Formation Through Chromatin Silencing of E2F1 Target Genes

Endorf

Qing

Aono

et al. 2017

ATVB

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“…However, mice deficient in telomere genes do not show any signs of lung fibrosis. When challenged with cigarette smoke, these mice develop emphysema, but when instilled with bleomycin, pulmonary fibrosis is either attenuated or not at all affected by telomerase deficiency [40,210]. In addition, a telomerase activator was recently shown to suppress pulmonary fibrosis in mice [211].…”

Section: Telomere Attritionmentioning

confidence: 99%

Hallmarks of the ageing lung

2015

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Ageing is the main risk factor for major non-communicable chronic lung diseases, including chronic obstructive pulmonary disease, most forms of lung cancer and idiopathic pulmonary fibrosis. While the prevalence of these diseases continually increases with age, their respective incidence peaks at different times during the lifespan, suggesting specific effects of ageing on the onset and/or pathogenesis of chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibrosis. Recently, the nine hallmarks of ageing have been defined as cell-autonomous and non-autonomous pathways involved in ageing. Here, we review the available evidence for the involvement of each of these hallmarks in the pathogenesis of chronic obstructive pulmonary disease, lung cancer, or idiopathic pulmonary fibrosis. Importantly, we propose an additional hallmark, "dysregulation of the extracellular matrix", which we argue acts as a crucial modifier of cell-autonomous changes and functions, and as a key feature of the above-mentioned lung diseases. @ERSpublications Hallmarks of ageing are selecting factors for the pathogenesis of COPD, lung cancer and IPF

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“…Specific mutation of genes considered to be a key factor in the origin and progression of cancer [12][13][14][15][16][17], such as p53, fragile histidine triad, microsatellite instability and loss of heterozygosity have been observed in ,50% of IPF patients and often described in the peripheral honeycomb areas characteristic of IPF [17][18][19][20]. Other mutations commonly associated with cancer initiation and development, such as telomere shortening and telomerase expression, have been described in familial and sporadic IPF [21][22][23]. More recently, the abnormal expression of mRNAs has also been associated with the pathogenesis of both cancer and IPF.…”

Section: Epigenetic and Genetic Abnormalities In Ipf And Cancermentioning

confidence: 99%

Common pathways in idiopathic pulmonary fibrosis and cancer

Vancheri¹

2013

Eur Respir Rev

149

105

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Idiopathic pulmonary fibrosis (IPF) is marked by a very disappointing survival rate and still represents a clinical dilemma. According to the current pathogenic hypothesis, chronic damage of the alveolar epithelium is followed by abnormal tissue repair and impairment of the alveolar structure. This process is driven by pathogenic events very similar to cancer, including epigenetic and genetic changes, altered response to regulatory signals, abnormal expression of microRNAs and activation of specific signalling pathways. IPF also resembles cancer with regard to its poor response to medical treatment and prognosis, which is very often worse than many cancers. We have hypothesised that IPF might be assimilated to a neoproliferative disorder of the lung. Viewing IPF as a cancer-like disease may satisfy the need for a better understanding of the pathogenesis of IPF by exploiting the large amount of knowledge that cancer biology evokes. The recognition of common pathogenic pathways between the two diseases may stimulate new clinical trials with cancer drugs, different drug combinations and different lines of drugs, as already experimented in oncology. Moreover, the concept of IPF as a cancer-like disorder may improve the attention given to this dreadful disease on a public, political and healthcare level. @ERSpublications Considering idiopathic pulmonary fibrosis as a cancer-like disorder may improve its treatment and investigation.

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Telomerase activity is required for bleomycin-induced pulmonary fibrosis in mice

Cited by 72 publications

References 53 publications

Telomerase Reverse Transcriptase Deficiency Prevents Neointima Formation Through Chromatin Silencing of E2F1 Target Genes

Telomerase Reverse Transcriptase Deficiency Prevents Neointima Formation Through Chromatin Silencing of E2F1 Target Genes

Hallmarks of the ageing lung

Common pathways in idiopathic pulmonary fibrosis and cancer

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