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HGNC Approved Gene Symbol: GABPB1
Cytogenetic location: 15q21.2 Genomic coordinates (GRCh38) : 15:50,275,389-50,355,198 (from NCBI)
The GA-binding protein (GABP) complex, which regulates cell cycle control, protein synthesis, and cellular metabolism, consists of a DNA-binding alpha subunit and a transactivating beta subunit. The GABP-alpha subunit is encoded by a single gene (GABPA; 600609), whereas different isoforms of the GABP-beta subunit are encoded by 2 distinct genes, GABPB1 and GABPB2 (621284). GABPB1 generates 2 predominant isoforms via alternative splicing: GABPB1L (originally named GABPB1 or GABPB1-1) and GABPB1S (originally named GABPB2 or GABPB1-2) (summary by Jing et al., 2008 and Yu et al., 2012).
Watanabe et al. (1993) cloned HeLA cell cDNAs encoding 3 subunits of GABP, which they called adenovirus E4 gene transcription factor-1 (E4TF1): a 60-kD subunit (E4TF1-60, or GABPA; 600609), a 53-kD subunit (E4TF1-53, or GABPB1-1), and a 47-kD subunit (E4TF1-47, or GABPB1-2). The predicted E4TF1-53 and E4TF1-47 subunits contain 383 and 347 amino acids, respectively, and are highly homologous. The N-terminal 332 amino acids of E4TF1-53 and E4TF1-47, including 4 tandemly repeated Notch motifs, are identical; the proteins differ at their C termini. Watanabe et al. (1993) stated that all 3 E4TF1 proteins show high homology with the corresponding rat GA-binding proteins.
By PCR of a HeLa cell library using degenerate primers designed from the amino acid sequences of purified proteins, Gugneja et al. (1995) cloned NRF2-beta-1 and -beta-2 and NRF2-gamma-1 and -gamma-2. These variants were originally thought to represent splice variants of 2 separate genes (NRF2-beta and NRF2-gamma, respectively). However, it was later determined that all 4 variants are encoded by a single gene, GABPB1 (Rosmarin, 2003).
Watanabe et al. (1993) determined that E4TF1-53 and E4TF1-47 do not bind DNA, but both associate with the DNA-binding E4TF1-60 subunit.
Gugneja et al. (1995) verified DNA-binding activity in the alpha subunit of NRF2. They found that the NRF2-beta or -gamma subunit variants were required for transcriptional activation and that the alpha subunit was transcriptionally inactive. The 4 NRF2-beta and -gamma variants were equally proficient in activating transcription in transfected cells when fused to a GAL4 (602518) DNA-binding domain.
Suzuki et al. (1998) reported that the GABPB variant containing a C-terminal leucine zipper motif, which they called GABP-beta, can homodimerize and form a transcriptionally active heterotetrameric complex with GABPA. The variant lacking this motif, which they called GABP-gamma, can form heterodimers but cannot form transcriptionally active heterotetramers with GABPA. Suzuki et al. (1998) determined that the GABP-beta and GABP-gamma isoforms both stabilize the DNA-binding affinity of GABPA by imparting a slower dissociation rate. Northern and Western blot analyses showed that GABP-beta and GABP-gamma are coexpressed at different ratios in several tissues and established cell lines. The 2 forms bound GABPA competitively in vitro, and cotransfection assays revealed that the ratio of GABP-beta to GABP-gamma affected transcription from a GABP-activated promoter.
Amen et al. (2021) noted that TERT (187270) promoter mutations common in glioblastoma (GBM; 137800) create a binding site for the GABP transcription factor complex, leading to reactivation of TERT, which is normally silenced in somatic cells. Using knockdown analysis, Amen et al. (2021) showed that TERT promoter mutations specifically led to increased binding of GABP1L-containing GABP complexes. GABPB1L knockout impaired near-term growth of GBM cells with TERT promoter mutations in vitro, and GABPB1L knockdown slowed the growth of established TERT-mutant GBM tumors in mice in vivo, significantly prolonging survival of the mice. However, loss of GABPB1L in TERT-mutant GBM cells upregulated expression of GABPB2, suggesting a compensatory mechanism for GABPB1L deletion in TERT mutant cells and a possible resistance mechanism for GABPB1L-targeting cancer therapies. Nevertheless, targeting GABPB1L to downregulate TERT expression appeared to promote GBM response to chemotherapy.
Stumpf (2024) mapped the GABPB gene to chromosome 15q21.2 based on an alignment of the GABPB sequence (GenBank AK303901) with the genomic sequence (GRCh38).
Sawada et al. (1995) originally mapped the E4TF1B gene to chromosome 7q11.21 by fluorescence in situ hybridization. However, this region contains a GABPA pseudogene rather than the GABPB gene (Luo et al., 1999; Rosmarin, 2003).
Yu et al. (2012) found that mice lacking both Gabpb1l and Gabpb2 were viable. Loss of Gabpb1l and Gabpb2 diminished the hematopoietic stem cell (HSC) pool in mice but did not affect HSC differentiation into myeloid or lymphoid progenitors, indicating that formation of GABP tetramers was not required for HSC differentiation but was important for HSC pool maintenance. Further analysis showed that Gabpb1l and Gabpb2 were also important for HSC self-renewal, repopulation capacity, survival, and quiescence. Gabpb1l and Gabpb2 also regulated self-renewal of leukemic stem cells, and analysis with a chronic myelogenous leukemia (CML; see 608232) mouse model showed that loss of Gabpb1l and Gabpb2 caused synergistic effects on CML drug treatment.
Amen, A. M., Fellmann, C., Soczek, K. M., Ren, S. M., Lew, R. J., Knott, G. J., Park, J. E., McKinney, A. M., Mancini, A., Doudna, J. A., Costello, J. F. Cancer-specific loss of TERT activation sensitizes glioblastoma to DNA damage. Proc. Nat. Acad. Sci. 118: e2008772118, 2021. [PubMed: 33758097] [Full Text: https://doi.org/10.1073/pnas.2008772118]
Gugneja, S., Virbasius, J. V., Scarpulla, R. C. Four structurally distinct, non-DNA-binding subunits of human nuclear respiratory factor 2 share a conserved transcriptional activation domain. Molec. Cell. Biol. 15: 102-111, 1995. [PubMed: 7799916] [Full Text: https://doi.org/10.1128/MCB.15.1.102]
Jing, X., Zhao, D. M., Waldschmidt, T. J., Xue, H. H. GABP-beta-2 is dispensible (sic) for normal lymphocyte development but moderately affects B cell responses. J. Biol. Chem. 283: 24326-24333, 2008. [PubMed: 18628204] [Full Text: https://doi.org/10.1074/jbc.M804487200]
Luo, M., Shang, J., Yang, Z., Simkevich, C. P., Jackson, C. L., King, T. C., Rosmarin, A. G. Characterization and localization to chromosome 7 of psi-hGABP-alpha, a human processed pseudogene related to the ets transcription factor, hGABP-alpha. Gene 234: 119-126, 1999. [PubMed: 10393246] [Full Text: https://doi.org/10.1016/s0378-1119(99)00167-5]
Rosmarin, A. G. Personal Communication. Baltimore, Md. 7/11/2003.
Sawada, J., Goto, M., Watanabe, H., Handa, H., Yoshida, M. C. Regional mapping of two subunits of transcription factor E4TF1 to human chromosome. Jpn. J. Cancer Res. 86: 10-12, 1995. [PubMed: 7737900] [Full Text: https://doi.org/10.1111/j.1349-7006.1995.tb02981.x]
Stumpf, A. M. Personal Communication. Baltimore, Md. 04/05/2024.
Suzuki, F., Goto, M., Sawa, C., Ito, S., Watanabe, H., Sawada, J., Handa, H. Functional interactions of transcription factor human GA-binding protein subunits. J. Biol. Chem. 273: 29302-29308, 1998. [PubMed: 9792629] [Full Text: https://doi.org/10.1074/jbc.273.45.29302]
Watanabe, H., Sawada, J., Yano, K.-I., Yamaguchi, K., Goto, M., Handa, H. cDNA cloning of transcription factor E4TF1 subunits with Ets and notch motifs. Molec. Cell. Biol. 13: 1385-1391, 1993. [PubMed: 8441384] [Full Text: https://doi.org/10.1128/mcb.13.3.1385-1391.1993]
Yu, S., Jing, X., Colgan, J. D., Zhao, D. M., Xue, H. H. Targeting tetramer-forming GABP-beta isoforms impairs self-renewal of hematopoietic and leukemic stem cells. Cell Stem Cell 11: 207-219, 2012. [PubMed: 22862946] [Full Text: https://doi.org/10.1016/j.stem.2012.05.021]