# Signaling Regulation of GABP-Mediated Mutant TERT Promoter Activation in Glioma

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $40,316

## Abstract

Project Summary
A hallmark of human cancers is their ability to avoid replicative senescence and achieve cellular immortality.
Over 90% of cancers achieve this through re-expression of telomerease reverse transcriptase (TERT). TERT
encodes the enzymatic component of the ribonucleoprotein complex telomerase, which extends chromosome
ends by adding repetitive sequences called telomeres. TERT is transcriptionally silenced in somatic cells, but
remains active in stem cells. Recently, non-coding mutations in the promoter of TERT were described in many
cancers, including 83% of glioblastoma (GBM), the most common and deadly adult brain tumor, and 80% of
oligodendroglioma. TERT promoter mutations are now considered the third most common mutations in human
cancer. These mutations serve to reactivate TERT through creation of a canonical E26 transformation specific
(ETS) binding motif for the transcription factor GA binding protein (GABP), which has been demonstrated by
our lab to be a necessary factor in TERT reactivation and maintaining cellular immortality. It is unclear if
genetic alterations in oncogenic signaling pathways cooperate with TERT promoter mutations to fully reactivate
telomerase.
Depleting the tetrameric subunit of GABP has been demonstrated to reverse cellular immortality in GBM.
However, transcription factors are notoriously difficult to target therapeutically and therefore additional means
of reducing GABP transcriptional activity at TERT are needed. Transcription of GABP and other ETS factors is
regulated by upstream signaling, and these pathways could be targeted as a means of inhibiting TERT. Thus
far, no upstream signaling pathways controlling TERT promoter activity have been described in glioma.
Preliminary evidence has revealed two candidate pathways altered in glioma—the tumor-promoting AMPK and
the tumor-suppressive CIC, that regulate the mutant TERT promoter. This study aims to delineate the role of
this pathways in telomere maintenance and cellular immortality. This research will deepen our understanding
of the functional role of non-coding mutations and GABP transcriptional regulation in cancer, and will provide
insights into different means of targeting GABP to reverse cellular immortality in GBM. Telomerase has long
been an attractive therapeutic option, but attempts to target telomerase have been largely unsuccessful, at
least in part due to depletion of TERT expressing stem cells. Understanding how tumor suppressive and tumor
promoting signaling pathways coordinate to activate the TERT promoter in a GABP-dependent manner would
provide novel therapeutic avenues for reversing cellular immortality in adult glioma in a cancer-specific
manner.

## Key facts

- **NIH application ID:** 9964492
- **Project number:** 5F31CA243187-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Andrew McKinney
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $40,316
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964492

## Citation

> US National Institutes of Health, RePORTER application 9964492, Signaling Regulation of GABP-Mediated Mutant TERT Promoter Activation in Glioma (5F31CA243187-02). Retrieved via MORVS 2026-10-27 from https://api.morvs.ai/grant/nih/9964492. Licensed CC0.

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