Direct activation of telomerase by EGF through Ets-mediated transactivation of TERT via MAP kinase signaling pathway

Abstract

Telomerase is a regulated enzyme and its activity is tightly associated with cell proliferation. The mechanisms of this association are unclear, but speci®c growth factors may regulate telomerase activity. The present study examines the eect of epidermal growth factor (EGF) on telomerase activity and identi®es the signal transduction pathway involved in this process. EGF upregulated telomerase activity in EGF receptor-positive cells after the activation of telomerase reverse transcriptase (TERT) mRNA expression. This activation was rapid, peaked after 6 or 12 h and was not blocked by the concurrent exposure to cycloheximide, suggesting a direct eect of EGF on TERT transcription. Transient expression assays revealed that EGF activates the hTERT promoter and that the proximal core promoter is responsible for this regulation. The activation of hTERT mRNA expression by EGF was speci®cally blocked by MEK inhibitor, and in vitro kinase assays demonstrated that ERK is activated in response to EGF. Transient expression assays using mutant reporter plasmids revealed that an ETS motif located in the core promoter of hTERT is required for the EGF-induced transactivation of hTERT. Overexpression of wild type Ets in cells enhanced the EGF eect on hTERT transcription, while that of dominant negative Ets signi®cantly repressed EGF action. These ®ndings suggest that EGF activates telomerase through the direct activation of TERT transcription, in which the Ras/ MEK/ERK pathway and Ets factor play major roles. Our data support the notion that growth factors directly regulate telomerase via speci®c signal transduction pathways.

Influence of the growth factors PDGF‐BB, TGF‐β1 and bFGF on the replicative aging of human articular chondrocytes during in vitro expansion

“…28 There is considerable evidence that growth factors are capable of mediating telomerase expression to regulate cell proliferation and differentiation during cell cycle and as well during malignant cell transformation processes. 19,[23][24][25][26][27][28][29] These studies were to investigate whether growth factors are able to accelerate cell proliferation potential, their impacts on telomere biology, and the gene-expression profile of matrix proteins.…”

“…[19][20][21] To shorten cell expansion periods for cell therapy and tissue engineering, cells may be cultured in the presence of recombinant growth factors. 4,22 There is, however, considerable evidence that growth hormones-such as epidermal growth factor (EGF) 23,24 insulin-like growth factor (IGF), 25,26 or transforming growth factor b (TGFb) [27][28][29] -profoundly affect mechanisms of cell cycle regulation. Thus, the specific objective of this study was to elucidate to which extend PDGF-BB (plateletderived growth factor), TGF-b1, and bFGF (basic fibroblast growth factor)-growth factors regularly used in chondrocyte culturing-may instigate replicative senescence or immortality of somatic cells by regulating telomerase activity.…”

Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

“…These include MAPK, transforming growth factor β (TGF-β) and NF-κB signalling pathways. Signals transmitted through MAPK family can increase or decrease hTERT transcription depending on different stimuli [51][52][53][54][55], whereas TGF-β inhibits hTERT gene transcription by Smad 3 signaling [56][57][58]. In addition, hTERT is also targeted for activation by several viral oncogenes including human papillomavirus (HPV) type-16 E6/E7 and simian virus 40 T antigens [59,60].…”

αCP1 Mediates Stabilization of hTERT mRNA by Autocrine Human Growth Hormone

“…The MCF-7 cells were cultured at 37°C in 5% CO 2 in RPMI supplemented with 10% heat-inactivated fetal bovine serum, 100 units/ml penicillin, and 100 g/ml streptomycin. Serum is a stimulator of hTERT transcription because of the presence of mitogens such as epidermal growth factor, insulinlike growth factor, and estrogens (24,28,29). We have utilized serum deprivation to minimize hTERT transcriptional activation in the experiments reported herein unless indicated otherwise.…”