ETS-dependent telomerase reactivation in human cancers
Abstract/Contents
- Abstract
- Telomerase is up-regulated in 90% of human tumors where it confers cellular immortality. Gliomas, melanomas, and cancers of the liver, bladder and thyroid, sustain highly recurrent mutations in the promoter of the gene encoding telomerase reverse transcriptase (TERT), whose transcription controls telomerase expression. These proximal promoter mutations, C124T and C146T, are the most common noncoding mutations in the human cancer genome. Each mutation creates a new DNA binding consensus site for ETS transcription factor GABP, but the requirement for GABP in telomerase function and cell immortalization remains unknown. In a larger context, transcriptional activation of TERT in cancers without promoter mutations has remained an intractable mystery. A detailed understanding of how TERT regulation in cancer compares to that in normal cells is also lacking. Closing these gaps of knowledge would greatly advance our understanding of the immortalization process and provide insights into therapeutic designs targeting telomerase in cancer. The work described here aims to answer the fundamental questions regarding the mechanisms governing telomerase reactivation in cancer. Using CRISPR mediated genome editing, here we show that GABP is not only indispensible for telomerase expression and immortality in TERT mutant cancers, but also necessary for TERT activation in TERT WT cancers. GABP activates wild type TERT promoter by binding to a conserved ETSbox. In TERT promoter mutant cancers, cooperation between ETSbox and the de novo ETS site is crucial in allowing heterotetramer formation of GABP. Furthermore, we demonstrate that GABP is not only required for TERT transcription in cancers but also in human and mouse embryonic stem cells. We propose that an evolutionarily conserved role of GABP in regulating TERT promoter in telomerase positive cells, and TERT promoter mutations operate by potentiating this mechanism through allowing heterotetramer formation and therefore stronger effects of GABP.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2017 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Yin, Yi |
|---|---|
| Associated with | Stanford University, Cancer Biology Program. |
| Primary advisor | Artandi, Steven E |
| Thesis advisor | Artandi, Steven E |
| Thesis advisor | Brunet, Anne, 1972- |
| Thesis advisor | Sage, Julien |
| Thesis advisor | Wernig, Marius |
| Advisor | Brunet, Anne, 1972- |
| Advisor | Sage, Julien |
| Advisor | Wernig, Marius |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Yi Alicia Yin. |
|---|---|
| Note | Submitted to the Program in Cancer Biology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2017. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2017 by Yi Yin
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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