GA-binding protein transcription factor (GABP)

GA-binding protein (GABP) is a heteromeric transcription factor and a member of the ETS (E26 transformation-specific) family, typically consisting of the DNA-binding GABPA subunit and the transactivating GABPB subunit (Bell et al., 2015, Science). In a significant portion of human cancers, including glioblastoma and melanoma, highly recurrent mutations in the hTERT promoter (notably C228T and C250T) create de novo ETS-binding motifs that are specifically recognized by GABP (Mancini et al., 2018, Cancer Cell). This recruitment leads to the reactivation of telomerase, a key step in oncogenesis that allows cancer cells to bypass replicative senescence and achieve immortality (Heidenreich & Kumar, 2017, Nature Reviews Cancer). While several ETS factors can theoretically bind these sites, GABP—and specifically the GABPB1L isoform—has been identified as the primary driver of mutant hTERT expression (Stern et al., 2015, Genes & Development). Consequently, GABP and its interaction with the mutant hTERT promoter represent a high-value precision oncology target. Therapeutic strategies currently under investigation include the use of antisense oligonucleotides to deplete GABPB1L and small molecules designed to disrupt the GABPA-GABPB1 protein-protein interaction (Vogelstein et al., 2013, Science). By targeting a mechanism unique to mutation-bearing tumor cells, these approaches aim to selectively inhibit telomerase while minimizing impact on normal somatic cells (Akıncılar et al., 2016, Nucleic Acids Res).

Other names

GA-binding proteinNuclear respiratory factor 2NRF-2E4TF1GABPA/GABPB complexETS-family transcription factor GABP

Inhibition of GABP complex assembly or DNA binding at mutant hTERT promoter ETS motifs to suppress telomerase expression and induce cancer cell senescence.