* 600609

GA-BINDING PROTEIN TRANSCRIPTION FACTOR, ALPHA SUBUNIT; GABPA


Alternative titles; symbols

GABP-ALPHA
NUCLEAR RESPIRATORY FACTOR 2, ALPHA SUBUNIT; NRF2A
ADENOVIRUS E4 GENE TRANSCRIPTION FACTOR, 60-KD SUBUNIT
E4TF1-60


HGNC Approved Gene Symbol: GABPA

Cytogenetic location: 21q21.3     Genomic coordinates (GRCh38): 21:25,734,972-25,772,460 (from NCBI)


TEXT

Description

The GA-binding protein transcription factor, also called nuclear respiratory factor-2 (NRF2), was originally identified by its role in the expression of the adenovirus E4 gene. The GABP complex contributes to the transcriptional regulation of a number of subunits of mitochondrial enzymes, including cytochrome c oxidase (CO; see 516030) and mitochondrial transcription factor A (TFAM; 600438).


Cloning and Expression

Watanabe et al. (1993) cloned HeLa cell cDNAs encoding 3 subunits of GABP, which they called E4TF1: GABPA, a 60-kD DNA-binding subunit, GABPB1, a 53-kD transcription-activating subunit, and GABPB2, a 47-kD subunit. (GABPB1 and GABPB2 were originally thought to be encoded by separate genes, but were later found to be encoded by a single gene, GABPB; see 600610.) The GABPA protein is closely related to the rat GA-binding protein alpha subunit, and the 53- and 47-kD proteins are related to the rat GABP beta subunits. Human GABPA has a DNA-binding motif characteristic of the ETS oncogene family (see 164720).

Gugneja et al. (1995) cloned GABPA, which they called NRF2-alpha, by PCR of a HeLa cell library, using degenerate primers designed from the amino acid sequence of the purified protein. Guo et al. (2000) cloned a partial alpha subunit from a human brain cDNA library by PCR using primers designed from the HeLa GABPA sequence.

GABPA Pseudogene

Luo et al. (1999) isolated a processed GABPA pseudogene that was expressed as RNA in a human myeloid cell line. They determined that the pseudogene is mutated at the ATG start codon, preventing its translation into protein.


Gene Function

Gugneja et al. (1995) verified-DNA binding activity in the alpha subunit of NRF2. They further found that the beta subunit was required for transcriptional activation and that the alpha subunit was transcriptionally inactive.

Virbasius and Scarpulla (1994) noted that nuclear-encoded mitochondrial transcription factor TFAM contains potential binding sites for NRF1 (600879) and NRF2 within the promoter region. With use of binding and electrophoretic mobility shift assays, DNase footprinting, and mutation analysis of recombinant proteins, they demonstrated specific and functional binding of NRF1 and NRF2 to the TFAM promoter region. Methylation of the guanine nucleotides in the GGAT sequence of the TFAM promoter interfered with NRF2 binding. With use of reporter constructs and mutation analysis, they determined that NRF2 had a more modest effect on TFAM promoter activity than NRF1.

By in situ hybridization of adult macaque striate cortex, Guo et al. (2000) found that the expression of NRF2A correlated with the activity of cytochrome c oxidase both spatially and temporally, under normal conditions and under conditions of visual deprivation. Guo et al. (2000) hypothesized that NRF2 may serve as a coordinator for the expression of the 13 CO subunits from the nuclear and mitochondrial genomes.

Using chromatin immunoprecipitation coupled with genomewide promoter microarrays to query endogenous promoter occupancy by 3 ETS1 proteins, ETS1 (164720), ELF1 (189973), and GABPA, in the Jurkat human T-cell line, Hollenhorst et al. (2007) found frequent redundant promoter occupancy and less frequent specific promoter occupancy. Redundant binding correlated with housekeeping classes of genes, whereas specific binding examples represented more specialized genes. Redundant binding correlated with consensus ETS-binding sequences near transcription start sites, whereas specific binding sites diverged dramatically from the consensus and were further from transcription start sites.

Reactivation of TERT (187270) expression enables cells to overcome replicative senescence and escape apoptosis, which are fundamental steps in the initiation of human cancer. Multiple cancer types, including up to 83% of glioblastomas (137800), harbor highly recurrent TERT promoter mutations of unknown function but specific to 2 nucleotide positions. Bell et al. (2015) identified the functional consequence of these mutations in glioblastomas to be recruitment of the multimeric GA-binding protein transcription factor (GABP) specifically to the mutant promoter. Allelic recruitment of GABP is consistently observed across 4 cancer types, highlighting a shared mechanism underlying TERT reactivation. Tandem flanking native E26 transformation-specific motifs critically cooperate with these mutations to activate TERT, probably by facilitating GABP heterotetramer binding. Bell et al. (2015) concluded that GABP directly links TERT promoter mutations to aberrant expression in multiple cancers.

Chen et al. (2019) found that GABPA regulates the differentiation of a novel subset of beige adipocytes through a myogenic intermediate. This beige fat, termed glycolytic beige fat, is distinct from conventional beige fat with respect to developmental origin and regulation, and displays enhanced glucose oxidation. Glycolytic beige fat has a critical role in chronic cold adaptation in the absence of beta-adrenergic receptor signaling.


Gene Structure

Goto et al. (1995) determined that the GABPA gene contains 10 exons and spans more than 35 kb.


Mapping

Sawada et al. (1995) mapped E4TF1A to 21q21 by FISH. In the course of exon trapping/amplification for cloning portions of genes from human chromosome 21, Chrast et al. (1995) found one trapped sequence that showed complete homology with nucleotide sequence D13318 of GenBank, which corresponded to the gene for human transcription factor E4TF1-60. By FISH, somatic cell hybrid analysis, and hybridization to chromosome 21-specific YACs, they mapped the gene to chromosome 21 and localized it to YACs 816B7 and 848G1 of the YAC contig, near the APP gene (104760) in 21q21-q22.1. The authors suggested that this transcription factor, which forms heterodimers with other polypeptides, may contribute in a gene dosage-dependent manner to the phenotype of Down syndrome.

By analyzing a human-rodent hybrid cell line containing only the long arm of chromosome 21, Goto et al. (1995) mapped the GABPA gene to chromosome 21q21.2-q21.3.

GABPA Pseudogene

By somatic cell hybrid analysis, Luo et al. (1999) mapped a processed GABPA pseudogene to chromosome 7.


REFERENCES

  1. Bell, R. J. A., Rube, H. T., Kreig, A., Mancini, A., Fouse, S. D., Nagarajan, R. P., Choi, S., Hong, C., He, D., Pekmezci, M., Wiencke, J. K., Wrensch, M. R., Chang, S. M., Walsh, K. M., Myong, S., Song, J. S., Costello, J. F. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science 348: 1036-1039, 2015. [PubMed: 25977370, images, related citations] [Full Text]

  2. Chen, Y., Ikeda, K., Yoneshiro, T., Scaramozza, A., Tajima, K., Wang, Q., Kim, K., Shinoda, K., Sponton, C. H., Brown, Z., Brack, A., Kajimura, S. Thermal stress induces glycolytic beige fat formation via a myogenic state. Nature 565: 180-185, 2019. [PubMed: 30568302, related citations] [Full Text]

  3. Chrast, R., Chen, H., Morris, M. A., Antonarakis, S. E. Mapping of the human transcription factor GABPA (E4TF1-60) gene to chromosome 21. Genomics 28: 119-122, 1995. [PubMed: 7590737, related citations] [Full Text]

  4. Goto, M., Shimizu, T., Sawada, J., Sawa, C., Watanabe, H., Ichikawa, H., Ohira, M., Ohki, M., Handa, H. Assignment of the E4TF1-60 gene to human chromosome 21.q21.2-q21.3. Gene 166: 337-338, 1995. [PubMed: 8543189, related citations] [Full Text]

  5. 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, related citations] [Full Text]

  6. Guo, A., Nie, F., Wong-Riley, M. Human nuclear respiratory factor 2-alpha subunit cDNA: isolation, subcloning, sequencing, and in situ hybridization of transcripts in normal and monocularly deprived macaque visual system. J. Comp. Neurol. 417: 221-232, 2000. [PubMed: 10660899, related citations] [Full Text]

  7. Hollenhorst, P. C., Shah, A. A., Hopkins, C., Graves, B. J. Genome-wide analyses reveal properties of redundant and specific promoter occupancy within the ETS gene family. Genes Dev. 21: 1882-1894, 2007. [PubMed: 17652178, images, related citations] [Full Text]

  8. 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, related citations] [Full Text]

  9. 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, related citations] [Full Text]

  10. Virbasius, J. V., Scarpulla, R. C. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc. Nat. Acad. Sci. 91: 1309-1313, 1994. [PubMed: 8108407, related citations] [Full Text]

  11. 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, related citations] [Full Text]


Ada Hamosh - updated : 03/07/2019
Ada Hamosh - updated : 07/01/2015
Patricia A. Hartz - updated : 8/31/2007
Patricia A. Hartz - updated : 7/11/2003
Patricia A. Hartz - updated : 6/28/2002
Patricia A. Hartz - updated : 6/20/2002
Creation Date:
Alan F. Scott : 6/14/1995
alopez : 03/07/2019
alopez : 07/01/2015
carol : 9/7/2007
terry : 8/31/2007
mgross : 7/11/2003
mgross : 7/11/2003
carol : 6/28/2002
carol : 6/24/2002
terry : 6/20/2002
carol : 6/13/2002
carol : 1/12/2000
alopez : 7/10/1997
mark : 7/3/1997
joanna : 6/24/1997
mark : 8/17/1995
mark : 6/14/1995

* 600609

GA-BINDING PROTEIN TRANSCRIPTION FACTOR, ALPHA SUBUNIT; GABPA


Alternative titles; symbols

GABP-ALPHA
NUCLEAR RESPIRATORY FACTOR 2, ALPHA SUBUNIT; NRF2A
ADENOVIRUS E4 GENE TRANSCRIPTION FACTOR, 60-KD SUBUNIT
E4TF1-60


HGNC Approved Gene Symbol: GABPA

Cytogenetic location: 21q21.3     Genomic coordinates (GRCh38): 21:25,734,972-25,772,460 (from NCBI)


TEXT

Description

The GA-binding protein transcription factor, also called nuclear respiratory factor-2 (NRF2), was originally identified by its role in the expression of the adenovirus E4 gene. The GABP complex contributes to the transcriptional regulation of a number of subunits of mitochondrial enzymes, including cytochrome c oxidase (CO; see 516030) and mitochondrial transcription factor A (TFAM; 600438).


Cloning and Expression

Watanabe et al. (1993) cloned HeLa cell cDNAs encoding 3 subunits of GABP, which they called E4TF1: GABPA, a 60-kD DNA-binding subunit, GABPB1, a 53-kD transcription-activating subunit, and GABPB2, a 47-kD subunit. (GABPB1 and GABPB2 were originally thought to be encoded by separate genes, but were later found to be encoded by a single gene, GABPB; see 600610.) The GABPA protein is closely related to the rat GA-binding protein alpha subunit, and the 53- and 47-kD proteins are related to the rat GABP beta subunits. Human GABPA has a DNA-binding motif characteristic of the ETS oncogene family (see 164720).

Gugneja et al. (1995) cloned GABPA, which they called NRF2-alpha, by PCR of a HeLa cell library, using degenerate primers designed from the amino acid sequence of the purified protein. Guo et al. (2000) cloned a partial alpha subunit from a human brain cDNA library by PCR using primers designed from the HeLa GABPA sequence.

GABPA Pseudogene

Luo et al. (1999) isolated a processed GABPA pseudogene that was expressed as RNA in a human myeloid cell line. They determined that the pseudogene is mutated at the ATG start codon, preventing its translation into protein.


Gene Function

Gugneja et al. (1995) verified-DNA binding activity in the alpha subunit of NRF2. They further found that the beta subunit was required for transcriptional activation and that the alpha subunit was transcriptionally inactive.

Virbasius and Scarpulla (1994) noted that nuclear-encoded mitochondrial transcription factor TFAM contains potential binding sites for NRF1 (600879) and NRF2 within the promoter region. With use of binding and electrophoretic mobility shift assays, DNase footprinting, and mutation analysis of recombinant proteins, they demonstrated specific and functional binding of NRF1 and NRF2 to the TFAM promoter region. Methylation of the guanine nucleotides in the GGAT sequence of the TFAM promoter interfered with NRF2 binding. With use of reporter constructs and mutation analysis, they determined that NRF2 had a more modest effect on TFAM promoter activity than NRF1.

By in situ hybridization of adult macaque striate cortex, Guo et al. (2000) found that the expression of NRF2A correlated with the activity of cytochrome c oxidase both spatially and temporally, under normal conditions and under conditions of visual deprivation. Guo et al. (2000) hypothesized that NRF2 may serve as a coordinator for the expression of the 13 CO subunits from the nuclear and mitochondrial genomes.

Using chromatin immunoprecipitation coupled with genomewide promoter microarrays to query endogenous promoter occupancy by 3 ETS1 proteins, ETS1 (164720), ELF1 (189973), and GABPA, in the Jurkat human T-cell line, Hollenhorst et al. (2007) found frequent redundant promoter occupancy and less frequent specific promoter occupancy. Redundant binding correlated with housekeeping classes of genes, whereas specific binding examples represented more specialized genes. Redundant binding correlated with consensus ETS-binding sequences near transcription start sites, whereas specific binding sites diverged dramatically from the consensus and were further from transcription start sites.

Reactivation of TERT (187270) expression enables cells to overcome replicative senescence and escape apoptosis, which are fundamental steps in the initiation of human cancer. Multiple cancer types, including up to 83% of glioblastomas (137800), harbor highly recurrent TERT promoter mutations of unknown function but specific to 2 nucleotide positions. Bell et al. (2015) identified the functional consequence of these mutations in glioblastomas to be recruitment of the multimeric GA-binding protein transcription factor (GABP) specifically to the mutant promoter. Allelic recruitment of GABP is consistently observed across 4 cancer types, highlighting a shared mechanism underlying TERT reactivation. Tandem flanking native E26 transformation-specific motifs critically cooperate with these mutations to activate TERT, probably by facilitating GABP heterotetramer binding. Bell et al. (2015) concluded that GABP directly links TERT promoter mutations to aberrant expression in multiple cancers.

Chen et al. (2019) found that GABPA regulates the differentiation of a novel subset of beige adipocytes through a myogenic intermediate. This beige fat, termed glycolytic beige fat, is distinct from conventional beige fat with respect to developmental origin and regulation, and displays enhanced glucose oxidation. Glycolytic beige fat has a critical role in chronic cold adaptation in the absence of beta-adrenergic receptor signaling.


Gene Structure

Goto et al. (1995) determined that the GABPA gene contains 10 exons and spans more than 35 kb.


Mapping

Sawada et al. (1995) mapped E4TF1A to 21q21 by FISH. In the course of exon trapping/amplification for cloning portions of genes from human chromosome 21, Chrast et al. (1995) found one trapped sequence that showed complete homology with nucleotide sequence D13318 of GenBank, which corresponded to the gene for human transcription factor E4TF1-60. By FISH, somatic cell hybrid analysis, and hybridization to chromosome 21-specific YACs, they mapped the gene to chromosome 21 and localized it to YACs 816B7 and 848G1 of the YAC contig, near the APP gene (104760) in 21q21-q22.1. The authors suggested that this transcription factor, which forms heterodimers with other polypeptides, may contribute in a gene dosage-dependent manner to the phenotype of Down syndrome.

By analyzing a human-rodent hybrid cell line containing only the long arm of chromosome 21, Goto et al. (1995) mapped the GABPA gene to chromosome 21q21.2-q21.3.

GABPA Pseudogene

By somatic cell hybrid analysis, Luo et al. (1999) mapped a processed GABPA pseudogene to chromosome 7.


REFERENCES

  1. Bell, R. J. A., Rube, H. T., Kreig, A., Mancini, A., Fouse, S. D., Nagarajan, R. P., Choi, S., Hong, C., He, D., Pekmezci, M., Wiencke, J. K., Wrensch, M. R., Chang, S. M., Walsh, K. M., Myong, S., Song, J. S., Costello, J. F. The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer. Science 348: 1036-1039, 2015. [PubMed: 25977370] [Full Text: https://doi.org/10.1126/science.aab0015]

  2. Chen, Y., Ikeda, K., Yoneshiro, T., Scaramozza, A., Tajima, K., Wang, Q., Kim, K., Shinoda, K., Sponton, C. H., Brown, Z., Brack, A., Kajimura, S. Thermal stress induces glycolytic beige fat formation via a myogenic state. Nature 565: 180-185, 2019. [PubMed: 30568302] [Full Text: https://doi.org/10.1038/s41586-018-0801-z]

  3. Chrast, R., Chen, H., Morris, M. A., Antonarakis, S. E. Mapping of the human transcription factor GABPA (E4TF1-60) gene to chromosome 21. Genomics 28: 119-122, 1995. [PubMed: 7590737] [Full Text: https://doi.org/10.1006/geno.1995.1117]

  4. Goto, M., Shimizu, T., Sawada, J., Sawa, C., Watanabe, H., Ichikawa, H., Ohira, M., Ohki, M., Handa, H. Assignment of the E4TF1-60 gene to human chromosome 21.q21.2-q21.3. Gene 166: 337-338, 1995. [PubMed: 8543189] [Full Text: https://doi.org/10.1016/0378-1119(95)00575-7]

  5. 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]

  6. Guo, A., Nie, F., Wong-Riley, M. Human nuclear respiratory factor 2-alpha subunit cDNA: isolation, subcloning, sequencing, and in situ hybridization of transcripts in normal and monocularly deprived macaque visual system. J. Comp. Neurol. 417: 221-232, 2000. [PubMed: 10660899] [Full Text: https://doi.org/10.1002/(sici)1096-9861(20000207)417:2<221::aid-cne7>3.0.co;2-4]

  7. Hollenhorst, P. C., Shah, A. A., Hopkins, C., Graves, B. J. Genome-wide analyses reveal properties of redundant and specific promoter occupancy within the ETS gene family. Genes Dev. 21: 1882-1894, 2007. [PubMed: 17652178] [Full Text: https://doi.org/10.1101/gad.1561707]

  8. 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]

  9. 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]

  10. Virbasius, J. V., Scarpulla, R. C. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc. Nat. Acad. Sci. 91: 1309-1313, 1994. [PubMed: 8108407] [Full Text: https://doi.org/10.1073/pnas.91.4.1309]

  11. 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]


Contributors:
Ada Hamosh - updated : 03/07/2019
Ada Hamosh - updated : 07/01/2015
Patricia A. Hartz - updated : 8/31/2007
Patricia A. Hartz - updated : 7/11/2003
Patricia A. Hartz - updated : 6/28/2002
Patricia A. Hartz - updated : 6/20/2002

Creation Date:
Alan F. Scott : 6/14/1995

Edit History:
alopez : 03/07/2019
alopez : 07/01/2015
carol : 9/7/2007
terry : 8/31/2007
mgross : 7/11/2003
mgross : 7/11/2003
carol : 6/28/2002
carol : 6/24/2002
terry : 6/20/2002
carol : 6/13/2002
carol : 1/12/2000
alopez : 7/10/1997
mark : 7/3/1997
joanna : 6/24/1997
mark : 8/17/1995
mark : 6/14/1995