# Project 2: The GABP-TERT axis in immortality of Oligodendroglioma and Glioblastoma

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $449,799

## Abstract

PROJECT SUMMARY/ABSTRACT
The goal of Project 2 is to understand how factors uniquely recruited to the mutant TERT promoter (TERTp)
together with factors that are native to the wildtype (WT) promoter activate TERT to achieve tumor cell
immortality. TERTp mutation occurs in nearly all glioblastoma (GBM) and oligodendroglioma (OD), enabling
tumor cells to become immortal. We showed that the mutations allow the GA-binding protein (GABP) to
aberrantly activate the mutant TERTp across many cancer types. In our preliminary data and new publication,
reduction of GABP in GBM causes decreased TERT and a gradual and nearly complete loss of viability in a
TERTp mutation-dependent manner. GABP is not normally present at the TERTp, however little else is known
about this newly discovered central node in tumor cell immortality. We have discovered two novel candidate
molecules - RNF2, an ubiquitin ligase that appears to drive activation of the mutant TERTp; and the tumor
suppressor CIC that represses WT and mutant TERTp, but is recurrently mutated in OD and downregulated in
GBM. Here, we will test the hypothesis that activation of the mutant TERTp and tumor immortality by GABP
involve critical contributions from mutant allele-specific factors and native factors. In Aim 1, we will define the
role of mutant-specific recruitment of RNF2 in promoting TERT expression and immortality. We will examine
RNF2 recruitment to, and regulation of mutant TERTp across GBM and OD cultures, determine if knockdown
of RNF2 alters telomerase activity, telomere length and tumor cell viability in vitro and tumorigenesis in vivo,
and if combined inhibition of GABP and RNF2 accelerates these processes. Potential resistance mechanisms
in tumors that grow despite reduced GABP will be addressed. In Aim 2, we will determine how WT and mutant
CIC regulates TERT expression and immortality. WT CIC suppresses transcription several ETS factors which
we previously demonstrated normally activate the WT and mutant TERT promoter. We will test CIC
suppression of TERT expression across GBM and OD cultures, then test whether the recurrent loss of function
mutations found in OD upregulate TERT, and which ETS factors mediate the effect. We will knockdown the
CIC-regulated ETS factors and determine if they alter telomerase activity, telomere length and tumor cell
immortality. In Aim 3, we propose to more broadly discover novel regulators of immortality using an in vivo
CRISPRi screen. The gene inhibition will be modeled in TERTp mutant GBM cells with and without GABP-
editing in order to identify factors that regulate cellular immortality in vivo either independently of or
synergistically with GABP. Our results in glioma will build upon the central node of TERT-GABP interaction
which we discovered, and may be relevant to the wider spectrum of TERTp mutant tumor types. By
contrasting mechanisms of TERT regulation in two clinically distinct glioma subtypes -OD and GBM- we will
identify TERTp regulatory mech...

## Key facts

- **NIH application ID:** 10225494
- **Project number:** 5P01CA118816-13
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Joseph F Costello
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $449,799
- **Award type:** 5
- **Project period:** 2007-07-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225494

## Citation

> US National Institutes of Health, RePORTER application 10225494, Project 2: The GABP-TERT axis in immortality of Oligodendroglioma and Glioblastoma (5P01CA118816-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10225494. Licensed CC0.

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