E2F1 acts as a negative feedback regulator of c-Myc-induced hTERT transcription during tumorigenesis

Abstract

Since induction of hTERT expression and subsequent telomerase activation play a critical role in the multistep process of tumorigenesis, a better understanding of hTERT regulation may provide not only a rationale for the molecular basis of cancer progression but also a path to the development of cancer prevention. The c-Myc oncoprotein can function effectively in activating the transcriptional expression of hTERT through E-box elements on its promoter. E2F transcription factor 1 (E2F1) was found to be a repressor of hTERT transcription by directly binding to its promoter, thereby inhibiting hTERT protein expression. For the extensively crosstalk between c-Myc and E2F1 signals, which is now known to be vital to cell fate, we speculated that E2F1 may play a negative regulatory role in c-Myc-induced hTERT transcription. In the present study, we chose to use human embryonic fibroblast cells as an experimental model system, and present evidence that the E2F1 transcription factor constitutes a negative regulatory system to limit c-Myc transcriptional activation of hTERT in normal cells. Furthermore, we demonstrated that upregulation of the miR-17-92 cluster (miR-20a/miR-17-5p) is involved in the regulation of E2F1-mediated negative feedback of the c-Myc/hTERT pathway. Our results not only reveal novel insights into how normal cells control the transmission of c-Myc-mediated oncogenic signals, but also further establish E2F1 as an important molecular target for cancer therapy.

Expression of pluripotency‐related genes is highly dependent on trichostatin A‐assisted epigenomic modulation of porcine mesenchymal stem cells analysed for apoptosis and subsequently used for generating cloned embryos

“…Furthermore, the results of our current investigation have proved that TSA‐based epigenomic modulation of BM‐MSCs gives rise to increased quantitative profiles of Survivin mRNA expression. Survivin, aside from playing a pivotal role in the inhibition of effector phase of caspase‐dependent or independent apoptosis, has been shown to exhibit a relatively high capability to the prevention of two major cellular ageing biomarkers (decrease in telomerase activity and increase in telomere attrition/abrasion), acting as an intrinsic agent upregulating specificity protein 1 (Sp1)‐ and c‐Myc‐mediated telomerase reverse transcriptase ( TERT ) gene expression (Endoh, Tsuji, Asanuma, Yagihashi, & Watanabe, ; Furuya, Tsuji, Kobayashi, & Watanabe, ; Zhang et al, ). Taking into account these facts, we think that enhanced transcriptional activities of Survivin gene and subsequently TERT gene promoters (Cheung, Cheng, Chang, Chen, & Chang, ; Nicholls, Li, Wang, & Liu, ; Zhang, Chen, Yang, & Fang, ) appear to not only contribute to elongate the telomeres and to stabilize and maintain the length of extended chromosome ends, but also facilitate and accelerate the rearrangement of epigenetic age of TSA‐treated BM‐MSCs.…”

Transcription Regulation of the Human Telomerase Reverse Transcriptase (hTERT) Gene

“…The overexpression of wildtype E2F1, but not its mutant, has been shown to downregulate hTERT promoter activity and telomerase activity. The effect of E2F1 on hTERT promoter has been proposed to counteract the activating effect of c-Myc on the regulatory region [100] and act downstream of the TGFβ signaling pathway as the expression of a dominant negative form of E2F1 resulted in the abrogation of the TGFβ-induced hTERT inhibition [111]. …”

Transcription factors that interact with p53 and Mdm2

“…Activator E2Fs transactivate S phase‐promoting genes, such as DNA polymerase α dihydrofolate reductase, and thymidine kinase . E2F1, the prototype of activator E2Fs, was found to be a repressor of hTERT transcription by directly binding to its promoter, thereby shortening telomere length by inhibiting hTERT protein expression . E2F1 also represses the transcription of tumor suppressor genes such as Dmp1 and ARH1 .…”

“…20,21 E2F1, the prototype of activator E2Fs, was found to be a repressor of hTERT transcription by directly binding to its promoter, thereby shortening telomere length by inhibiting hTERT protein expression. 24 E2F1 also represses the transcription of tumor suppressor genes such as Dmp1 and ARH1. 25 Among E2F proteins, only E2F1-3a has a nuclear localization signal and interacts with p53.…”