The structure of GABPα/β: An ETS domain-ankyrin repeat heterodimer bound to DNA. Science 279, 1037-1041

Department of Biophysics and Biophysical Chemistry, Johns Hopkins University, Baltimore, Maryland, United States
Science (Impact Factor: 31.48). 03/1998; 279(5353):1037-41. DOI: 10.1126/science.279.5353.1037
Source: PubMed

ABSTRACT GA-binding protein (GABP) is a transcriptional regulator composed of two structurally dissimilar subunits. The α subunit contains
a DNA-binding domain that is a member of the ETS family, whereas the β subunit contains a series of ankyrin repeats. The crystal
structure of a ternary complex containing a GABPα/β ETS domain–ankyrin repeat heterodimer bound to DNA was determined at 2.15
angstrom resolution. The structure shows how an ETS domain protein can recruit a partner protein using both the ETS domain
and a carboxyl-terminal extension and provides a view of an extensive protein-protein interface formed by a set of ankyrin
repeats. The structure also reveals how the GABPα ETS domain binds to its core GGA DNA-recognition motif.

    • "It contains the transactivation (TAD) and nuclear localization signal (NLS) domains, whereas it does not physically interact with DNA [12] [13] [14]. Thus, both heteromer-forming subunits share an obligate codependence , a unique phenomenon among the ETS transcription factor family [11] [14]. GABP was described to influence the development and lineage commitment in lymphoid as well as myeloid compartments [15] [16] [17] [18]. "
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    ABSTRACT: In Philadelphia-positive chronic myeloid leukemia (CML), imatinib resistance frequently emerges due to point mutations in the ABL1 kinase domain, but may also be the consequence of uncontrolled upstream signaling. Recently, the heteromeric transcription factor GA-binding protein (GABP) was shown to promote CML-like myeloproliferative disease in mice. In a cohort of 70 CML patients, we demonstrate that expression of the GABP alpha subunit (GABPα) is positively correlated to the BCR-ABL1/ABL1 ratio. Moreover, significantly higher GABPα expression was detected in blast crisis than in chronic phase CML after performing data mining on 91 CML patients. In functional studies, imatinib sensitivity is enhanced after GABPα knockdown in TKI-sensitive K-562 as well as by overexpression of a deletion mutant in TKI-resistant NALM-1 cells. Moreover, in K-562 cells GABP-dependent expression variations of PRKD2 and RAC2, relevant signaling mediators in CML, were observed. Notably, Prkd2 was reported to be a GABP target gene in mice. In line with this, we detected a positive correlation of GABPA and PRKD2 expression in primary human CML, indicating that the effects of GABP are mediated by PRKD2. These findings illustrate an important role of GABP for disease development and imatinib sensitivity in human CML. Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.
    Experimental hematology 06/2015; DOI:10.1016/j.exphem.2015.05.011 · 2.81 Impact Factor
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    • "The functional NRF-2 protein is a heterodimer or a heterotetramer of the α and β subunits [41]. The α subunit contains the DNA binding domain that binds to the GGAA cis-element [41] [42]. The β subunit contains the transactivating domain and mediates heterodimer (αβ) or heterotetramer (α 2 β 2 ) formation, the latter being induced by homodimerization of two β subunits [42] [43]. "
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    ABSTRACT: Neuronal activity is highly dependent on energy metabolism. Nuclear respiratory factor 2 (NRF-2) tightly couples neuronal activity and energy metabolism by transcriptionally co-regulating all 13 subunits of an important energy-generating enzyme, cytochrome c oxidase (COX), as well as critical subunits of excitatory NMDA receptors. AMPA receptors are another major class of excitatory glutamatergic receptors that mediate most of the fast excitatory synaptic transmission in the brain. They are heterotetrameric proteins composed of various combinations of GluA1-4 subunits, with GluA2 being the most common one. We have previously shown that GluA2 (Gria2) is transcriptionally regulated by nuclear respiratory factor 1 (NRF-1) and specificity protein 4 (Sp4), which also regulate all subunits of COX. However, it was not known if NRF-2 also couples neuronal activity and energy metabolism by regulating subunits of the AMPA receptors. By means of multiple approaches, including electrophoretic mobility shift and supershift assays, chromatin immunoprecipitation, promoter mutations, real-time quantitative PCR, and western blot analysis, NRF-2 was found to functionally regulate the expression of Gria2, but not of Gria1, Gria3, or Gria4 genes in neurons. By regulating the GluA2 subunit of the AMPA receptor, NRF-2 couples energy metabolism and neuronal activity at the transcriptional level through a concurrent and parallel mechanism with NRF-1 and Sp4.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 09/2014; 1843(12). DOI:10.1016/j.bbamcr.2014.09.006 · 5.30 Impact Factor
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    • "The ETS-factor GABPα is a subunit of GABP (also known as nuclear respiratory factor 2 (1,2)), which is an obligate heterotetramer consisting of two GABPα and two GABPβ subunits (3–8). GABPα contains an ETS DNA-binding domain near the carboxy terminus and a pointed domain near the N-terminus. "
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    ABSTRACT: In prostate cancer (PC), the androgen receptor (AR) is a key transcription factor at all disease stages, including the advanced stage of castrate-resistant prostate cancer (CRPC). In the present study, we show that GABPα, an ETS factor that is up-regulated in PC, is an AR-interacting transcription factor. Expression of GABPα enables PC cell lines to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes. GABPα has a transcriptional role that dissects the overlapping cistromes of the two most common ETS gene fusions in PC: overlapping significantly with ETV1 but not with ERG target genes. GABPα bound predominantly to gene promoters, regulated the expression of one-third of AR target genes and modulated sensitivity to AR antagonists in hormone responsive and castrate resistant PC models. This study supports a critical role for GABPα in CRPC and reveals potential targets for therapeutic intervention.
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