TOX defines a conserved subfamily of HMG-box proteins

O'Flaherty, E; Kaye, Jonathan

doi:10.1186/1471-2164-4-13

Cited by 104 publications

(88 citation statements)

References 50 publications

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“…Rather, the HMG box domain of TOX is required for protein:protein associations with KU70/KU80 and functionally impairs recruitment of NHEJ factors to breaks. TOX contains a single highly conserved HMG box motif that is structurally distinct from both class I and II HMG box group containing proteins (38). Class I HMG box group proteins are transcription factors and contain a single HMG box that binds DNA in a sequence-specific manner.…”

Section: Discussionmentioning

confidence: 99%

TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia

et al. 2017

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T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive malignancy of thymocytes. Using a transgenic screen in zebrafish, thymocyte selection-associated high mobility box protein (TOX) was uncovered as a collaborating oncogenic driver that accelerated T-ALL onset by expanding the initiating pool of transformed clones and elevating genomic instability. TOX is highly expressed in a majority of human T-ALL and is required for proliferation and continued xenograft growth in mice. Using a wide array of functional analyses, we uncovered that TOX binds directly to KU70/80 and suppresses recruitment of this complex to DNA breaks to inhibit Non-Homologous End Joining repair (NHEJ). Impaired NHEJ is well known to cause genomic instability, including development of T cell malignancies in Ku70 and Ku80 deficient mice. Collectively, our work has uncovered important roles for TOX in regulating NHEJ by elevating genomic instability during leukemia initiation and sustaining leukemic cell proliferation following transformation.

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Section: Discussionmentioning

confidence: 99%

TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia

et al. 2017

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“…The female-specific expression of Tox and Trim24 requires GH and is dependent on two important global regulators of sex-specific liver gene expression, STAT5 and HNF4␣ (23). Tox is an HMG box protein that is expressed primarily in the thymus, liver, and brain (37). Trim24 can repress retinoic acid receptor transcriptional activity, and Trim24 deficiency in mice leads to increased retinoic acid signaling associated with development of hepatocellular carcinoma (11), which is more prevalent in male liver, where Trim24 is expressed at a low level compared to that in female liver (23).…”

Section: Discussionmentioning

confidence: 99%

Impact of CUX2 on the Female Mouse Liver Transcriptome: Activation of Female-Biased Genes and Repression of Male-Biased Genes

Conforto

Zhang

Sherman

et al. 2012

Molecular and Cellular Biology

122

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The growth hormone-regulated transcription factors STAT5 and BCL6 coordinately regulate sex differences in mouse liver, primarily through effects in male liver, where male-biased genes are upregulated and many female-biased genes are actively repressed. Here we investigated whether CUX2, a highly female-specific liver transcription factor, contributes to an analogous regulatory network in female liver. Adenoviral overexpression of CUX2 in male liver induced 36% of female-biased genes and repressed 35% of male-biased genes. In female liver, CUX2 small interfering RNA (siRNA) preferentially induced genes repressed by adenovirus expressing CUX2 (adeno-CUX2) in male liver, and it preferentially repressed genes induced by adeno-CUX2 in male liver. CUX2 binding in female liver chromatin was enriched at sites of male-biased DNase hypersensitivity and at genomic regions showing male-enriched STAT5 binding. CUX2 binding was also enriched near genes repressed by adeno-CUX2 in male liver or induced by CUX2 siRNA in female liver but not at genes induced by adeno-CUX2, indicating that CUX2 binding is preferentially associated with gene repression. Nevertheless, direct CUX2 binding was seen at several highly female-specific genes that were positively regulated by CUX2, including A1bg, Cyp2b9, Cyp3a44, Tox, and Trim24. CUX2 expression and chromatin binding were high in immature male liver, where repression of adult male-biased genes and expression of adult femalebiased genes are common, suggesting that the downregulation of CUX2 in male liver at puberty contributes to the developmental changes establishing adult patterns of sex-specific gene expression. S ex differences in liver gene expression are widespread and affect a broad range of physiological processes, including steroid and drug metabolism, pheromone binding, and lipid metabolism. Hepatic sex-biased genes are regulated by growth hormone (GH) (35, 49), which is secreted by the pituitary gland in a sex-specific manner in rats, mice, and humans (16,28,44,53). Pituitary GH secretion is highly pulsatile in adult male rats and mice, where strong plasma peaks of GH are followed by periods when GH levels are below detection, whereas GH secretion is more frequent in females, resulting in a more continuous exposure to circulating GH. These sexually dimorphic plasma GH patterns stimulate sex differential patterns of tyrosine phosphorylation/activation and nuclear translocation of the transcription factors STAT5a and STAT5b (collectively, STAT5) (50). Thus, STAT5 activation is persistent in female liver but is intermittent in male liver, where it coincides with the onset of each plasma GH pulse (4, 43, 54). STAT5 positively regulates ϳ90% of male-biased genes and negatively regulates ϳ60% of female-biased genes in male mouse liver (5). STAT5 binding sites are found near 35 to 40% of sex-specific genes, suggesting they are directly regulated by STAT5 (54). However, a majority of sex-specific genes do not respond rapidly to GH-activated STAT5, suggesting indirect regulatory mechani...

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“…The TFS2N domain is found in transcription elongation factor S-II, elongin A, and mediator complex subunit 26 and is implicated in the transcriptional initiation or elongation of RNA pol II (19). Tox4, a member of the TOX high mobility group box subfamily, possesses an high mobility group box implicated in protein-protein interactions and binding to bent or distorted DNA, such as four-way DNA junctions (53). The PP1 catalytic subunit harbors the catalytic domain specific to phosphorylated serine or threonine (1-3).…”

Section: Affinity Purification and Identification Of Wdr82-associatedmentioning

confidence: 99%

Identification and Characterization of a Novel Human PP1 Phosphatase Complex

Lee

You²,

Dobrota

et al. 2010

Journal of Biological Chemistry

123

155

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Mammalian Wdr82 is a regulatory component of the Setd1a and Setd1b histone H3-lysine 4 methyltransferase complexes and is implicated in the tethering of Setd1 complexes to transcriptional start sites of active genes. In the studies reported here, immunoprecipitation and mass spectrometry analyses reveal that Wdr82 additionally associates with multiple protein complexes, including an RNA polymerase II complex, four distinct histone H3-Lys 4 methyltransferase complexes, protein phosphatase 1 (PP1)-associated proteins, a chaperonin-containing Tcp1 complex, and other uncharacterized proteins. Further characterization of the PP1-associated proteins identified a stable multimeric complex composed of regulatory subunits PNUTS, Tox4, and Wdr82 and a PP1 catalytic subunit (denoted as the PTW/PP1 phosphatase complex). The PTW/ PP1 complex exhibits in vitro phosphatase activity in a PP1-dependent manner. Analysis of protein-protein interactions reveals that PNUTS mediates phosphatase complex formation by providing a binding platform to each component. The PNUTS and Tox4 subunits are predominantly associated with the PTW/PP1 phosphatase complex in HEK293 cells, and the integrity of this complex remains intact throughout cell cycle progression. Inducible expression of a PP1 interaction-defective form of PNUTS (W401A) or small interfering RNA-mediated depletion of PNUTS in HEK293 cells causes cell cycle arrest at mitotic exit and apoptotic cell death. PNUTS (W401A) shows normal association with chromosomes but causes defects in the process of chromosome decondensation at late telophase. These data reveal that mammalian Wdr82 functions in a variety of cellular processes and reveal a potential role of the PTW/PP1 phosphatase complex in the regulation of chromatin structure during the transition from mitosis into interphase. Protein phosphatase 1 (PP1)2 is a serine/threonine protein phosphatase involved in diverse cellular processes, such as transcription, replication, pre-mRNA splicing, protein synthesis, muscle contraction, carbohydrate metabolism, neuronal signaling, cell survival, and cell cycle progression (1-3). Mammals express three PP1 catalytic isoforms, PP1␣, PP1␥, and PP1␤/, which show distinct subcellular localization patterns (4, 5). PP1 catalytic isoforms do not exist freely in cells but rather associate with regulatory subunits to form distinct multimeric holoenzymes. In general, PP1 regulatory subunits function as signaling modules by regulating the enzymatic activity or targeting of catalytic subunits to specific substrates (6, 7). PP1 is involved in cell cycle progression, especially during mitosis and mitotic exit, and dysregulation of PP1 activity causes mitotic arrest or deficient cytokinesis in mammals (3,8,9). PP1 is associated with multiple mitotic structures, such as chromosomes, centrosomes, and spindles (4, 8, 10), and is implicated as a major phosphatase acting on phosphoproteins at mitotic exit (11-14). However, the specific regulatory or targeting subunits required for this activity are not well und...

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TOX defines a conserved subfamily of HMG-box proteins

Cited by 104 publications

References 50 publications

TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia

TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia

Impact of CUX2 on the Female Mouse Liver Transcriptome: Activation of Female-Biased Genes and Repression of Male-Biased Genes

Identification and Characterization of a Novel Human PP1 Phosphatase Complex

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