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PubMed2004

Alterations in the expression of DEAD-box and other RNA binding proteins during HIV-1 replication.

Recent results showed that certain DEAD box protein RNA helicases, DDX3 and DDX1, play an important role in the HIV infection cycle by facilitating the export of long, singly spliced or unspliced HIV RNAs from the nucleus via the CRM1-Rev pathway. Close examination of an extensive microarray expression profiling dataset obtained from cells latently infected with HIV induced to undergo lytic viral replication indicated that additional DEAD box proteins, beyond DDX3 and DDX1, exhibit differential expression during lytic HIV replication, and in latently infected cells prior to induction into active replication. This finding provides additional evidence that the involvement of DEAD box proteins and other RNA-binding proteins may play roles in active HIV replication and in the control of viral latency. Agents targeting these functions may offer new approaches to antiretroviral therapy and the therapeutic manipulation of HIV latency.

DEAD-box RNA Helicases↗

PubMed2002

The T-box family.

SUMMARY: Transcription factors of the T-box family are required both for early cell-fate decisions, such as those necessary for formation of the basic vertebrate body plan, and for differentiation and organogenesis. When mutated, T-box genes give dramatic phenotypes in mouse and zebrafish, and they have been implicated both in fundamentals of limb patterning and in a number of human congenital malformations such as Holt-Oram, ulnar-mammary and DiGeorge syndromes, as well as being amplified in a subset of cancers. Genes encoding members of the T-box family have recently been shown to comprise approximately 0.1% of genomes as diverse as those of nematodes and humans and have been identified in a wide variety of animals from ctenophores (comb jellies) to mammals; they are, however, completely absent from genomes from other organisms (such as the model plant Arabidopsis thaliana).

Animals↗

PubMed2005

Three new novel point mutations localized within and downstream of high-mobility group-box region in SRY gene in three Indian females with Turner syndrome.

Point mutations and deletions in the SRY gene result in XY sex reversal in pure gonadal dysgenesis. To date, a majority of these affect the high-mobility group (HMG) domain of SRY, which plays a key role in its DNA binding activity. We carried out molecular genetics studies in three Turner syndrome patients all presenting with 45,X/46,XY mosaic karyotype. Case 1 demonstrated an insertion of T (thymine) within helix I of HMG box leading to frame shift mutation (N82X). In case 2, insertion of A (adenine) downstream of HMG box resulted in a nonsense frame shift mutation (L159fsX167). These mutations resulted in truncated and altered proteins. In case 3, G>C missense mutation is found at codon 74 within helix I of HMG box (Q74H). No other mutations were found in the SRY gene of these patients. An allele-specific oligonucleotide study further confirmed that these variants are not common polymorphisms. To our knowledge, this is the first time these mutations are described at these codons resulting in mutated SRY proteins. Lack of a second sex chromosome in a majority of cells [mosaic karyotype and mutation(s) in the SRY gene] in these patients may have triggered the short stature.

Adult↗

PubMed2001

Determinants of T box protein specificity.

Members of the T box family of transcription factors play important roles in early development. Different members of the family exert different effects and here we show that much of the specificity of the Xenopus T box proteins Xbra, VegT and Eomesodermin resides in the DNA-binding domain, or T box. Binding site selection experiments show that the three proteins bind the same core sequence, but they select paired sites that differ in their orientation and spacing. Lysine 149 of Xbra is conserved in all Brachyury homologues, while the corresponding amino acid in VegT and Eomesodermin is asparagine. Mutation of this amino acid to lysine changes the inductive abilities of VegT and Eomesodermin to resemble that of Xbra.

Amino Acid Sequence↗

PubMed2002

The T-box transcription factor Brachyury mediates cartilage development in mesenchymal stem cell line C3H10T1/2.

The BMP2-dependent onset of osteo/chondrogenic differentiation in the acknowledged pluripotent murine mesenchymal stem cell line (C3H10T1/2) is accompanied by the immediate upregulation of Fibroblast Growth Factor Receptor 3 (FGFR3) and a delayed response by FGFR2. Forced expression of FGFR3 in C3H10T1/2 is sufficient for chondrogenic differentiation, indicating an important role for FGF-signaling during the manifestation of the chondrogenic lineage in this cell line. Screening for transcription factors exhibiting a chondrogenic capacity in C3H10T1/2 identified that the T-box containing transcription factor Brachyury is upregulated by FGFR3-mediated signaling. Forced expression of Brachyury in C3H10T1/2 was sufficient for differentiation into the chondrogenic lineage in vitro and in vivo after transplantation into muscle. A dominant-negative variant of Brachyury, consisting of its DNA-binding domain (T-box), interferes with BMP2-mediated cartilage formation. These studies indicate that BMP-initiated FGF-signaling induces a novel type of transcription factor for the onset of chondrogenesis in a mesenchymal stem cell line. A potential role for this T-box factor in skeletogenesis is further delineated from its expression profile in various skeletal elements such as intervertebral disks and the limb bud at late stages (18.5 d.p.c.) of murine embryonic development.

Animals↗

PubMed2006

Math1 target genes are enriched with evolutionarily conserved clustered E-box binding sites.

The basic helix-loop-helix (bHLH) transcription factor Math1 and its orthologs are fundamental for proper development of various neuronal subpopulations, such as cerebellar granule cells, D1 interneurons in the spinal cord, and inner ear hair cells. Although crucial for neurogenesis, the mechanisms by which Math1 specifically recognizes its direct targets are not fully understood. To search for direct and indirect target genes and signaling pathways controlled by Math1, we analyzed the effect of Math1 knockout on the expression profile of multiple genes in the embryonic cerebellum. Eighteen differentially expressed transcripts were identified and found to belong to a few developmentally-related functional groups, such as transcriptional regulation, proliferation, organogenesis, signal transduction, and apoptosis. Importantly, genomic analysis of E-box motifs has identified a significant enrichment and clustering of MATH1-binding E-boxes only in a subset of differentially expressed genes (Nr2f6, Hras1, and Hes5) in both mouse and man. Moreover, Math1 was shown by chromatin immunoprecipitation (ChIP) to bind, and by a luciferase reporter assay to activate transcription, of an upstream genomic fragment of Nr2f6. Taken together, we propose that when putative direct targets of Math1 are being selected for detailed studies on DNA microarray hybridization, the enrichment and clustering of binding E-boxes in multiple species may be helpful criteria. Our findings may be useful to the study of other bHLH transcription factors, many of which control the development of the nervous system.

Animals↗

PubMed2006

Xtbx6r, a novel T-box gene expressed in the paraxial mesoderm, has anterior neural-inducing activity.

T-box proteins are important transcriptional regulators in animal development. We searched the Xenopus laevis expressed sequence tag (EST) database using zebrafish tbx24 (Ztbx24) as a query and found a sequence. We then obtained corresponding clones from a neurula cDNA library. This novel gene has a T-box showing 53% homology with Xenopus laevis tbx6 (Xtbx6) and 51% with Ztbx24 at the amino acid level and is relatively close to Xtbx6 indicated by alignment analysis. In situ hybridization showed that it is expressed in the paraxial mesoderm in the caudal region in a very similar manner to Xtbx6, with a slight difference in that the former is emphasized more dorsally and has a more restricted distribution along the antero-posterior axis. From these results we named this gene Xtbx6r (tbx6-related). Xtbx6r or Xtbx6r-EnR, when overexpressed in animal caps, induced anterior neural markers but not mesodermal markers. In contrast, Xtbx6r-VP16, Xtbx6 and Ztbx24 induced various mesodermal markers. These results indicate that Xtbx6r is a transcriptional repressor and has activity different from that of Xtbx6 or Ztbx24. Xtbx6r induced Otx2, XAG and Pax6 in animal caps. This activity differed from that of Xbra-EnR or Xtbx6-EnR, suggesting that some differences in biological activity exist among the tested repressor-type T-box genes. Depletion of Xtbx6r by antisense morpholino oligo produced curved embryos, but did not affect expressions of MyoD, Myf5, XWnt8 or thylacine2, nor inhibited muscle differentiation or segmentation. The results of knockdown and overexpression experiments suggest that Xtbx6r is involved in some morphogenesis in the paraxial mesoderm.

Amino Acid Sequence↗

PubMed2002

Evidence that E-box promoter elements and MyoD transcription factors play a role in the induction of cathepsin B gene expression during human myoblast differentiation.

HB13 human myoblasts express physiological and biochemical markers associated with myoblast differentiation in non-human cell culture model systems. During differentiation, HB13 myoblasts also demonstrate fusion-related increases in cathepsin B activity and protein levels. These increases are associated with an increase in levels of cathepsin B mRNA suggesting the involvement of transcriptional regulatory mechanisms. To examine these mechanisms human myoblasts were transfected with cathepsin B nested deletion promoter constructs within the 1.8 kb 5' promoter 1 region of the human catB gene. Transfected myoblasts that were maintained under differentiating conditions demonstrated higher promoter activity than those maintained in proliferating conditions. The highest activity was obtained with pSCB2-3 (-1279/+56 bp), a construct containing two putative upstream E-box elements. Co-transfection experiments demonstrated that MyoD and myogenin transactivate cathepsin B promoter activity. Electrophoretic mobility shift assays of nuclear extracts incubated with an oligonucleotide containing two upstream E-box elements found within the cathepsin B promoter demonstrated two band shifts. The band shifts were abolished using an oligonucleotide with mutations in both E-box elements. Moreover, the shifted bands were super-shifted and abolished when incubated with anti-myogenin and anti-MyoD, respectively. Collectively, these data support myogenic transcription factor-mediated activation of cathepsin B expression during myogenesis.

Blotting, Northern↗

PubMed2006

Stepwise bending of DNA by a single TATA-box binding protein.

The TATA-box binding protein (TBP) is required by all three eukaryotic RNA polymerases for the initiation of transcription from most promoters. TBP recognizes, binds to, and bends promoter sequences called "TATA-boxes" in the DNA. We present results from the study of individual Saccharomyces cerevisiae TBPs interacting with single DNA molecules containing a TATA-box. Using video microscopy, we observed the Brownian motion of beads tethered by short surface-bound DNA. When TBP binds to and bends the DNA, the conformation of the DNA changes and the amplitude of Brownian motion of the tethered bead is reduced compared to that of unbent DNA. We detected individual binding and dissociation events and derived kinetic parameters for the process. Dissociation was induced by increasing the salt concentration or by directly pulling on the tethered bead using optical tweezers. In addition to the well-defined free and bound classes of Brownian motion, we observed another two classes of motion. These extra classes were identified with intermediate states on a three-step, linear-binding pathway. Biological implications of the intermediate states are discussed.

Binding Sites↗

PubMedDate not supplied

Neurological sequelae of boxing.

Blunt trauma to the head results in acceleration of the brain within the skull. This takes 2 forms: linear or translational acceleration which produces focal lesions, and rotational acceleration which results in 'sheering stresses' with stretching of nerves and bridging veins. Deceleration of the brain within the skull occurs when the head strikes a stationary object (e.g. floor, ring post). Cerebrovascular events are not infrequently encountered. The most common vascular sequalae is the subdural haematoma, which is also the most frequent cause of death in boxers. Epidural bleeds rare, and are generally due to deceleration of the brain. Subarachnoid bleeds have been rarely reported, but, like intraparenchymal haemorrhages, they do occur. Sudden flexion/extension of the neck is suggested as the mechanism of the occasional brainstem haemorrhage reported in boxing. Thrombosis of the internal carotid artery can occur secondary to direct blows to the neck or stretching of the contralateral carotid artery. The best known sequalae of boxing is traumatic encephalopathy--the 'punch drunk' syndrome. This is most common in second-rate and slugging type fighters. Severity correlates with the length of a boxer's career and total number of bouts, with an incidence of approximately 18%. Three stages of clinical deterioration are seen, the encephalopathy may be progressive or may remain clinically stable at any level. The first stage consists of affective disturbances with psychiatric symptoms being most marked. During the second stage an accentuation of the psychiatric symptoms occurs and signs/symptoms of Parkinsonism develop. The final stage consists of a decrease in general cognitive function together with pyramidal tract disease. Generally 2 to 3 years elapse between the first and final stages. Neuropathological studies reveal abnormalities of the septum pellucidum, scarring of the cerebellar and cerebral cortices, and loss of pyramidal neurons in the substantia nigra with neurofibrillary tangles in the absence of senile plaques. A 'groggy state' can occur in some fighters with confusion, impaired active attention and alteration of consciousness. During this period the boxer is at greater risk to suffer brain injury as defensive reflexes are frequently lost. Other neurological syndromes have been reported in addition to the 'groggy state'. These include a midbrain syndrome, headaches and cervical spinal injuries. Additionally, boxing appears to be a significant risk factor for the development of meningiomas.(ABSTRACT TRUNCATED AT 400 WORDS)

Athletic Injuries↗

PubMed2002

Physiological factors in middleweight boxing performance.

BACKGROUND: We examined, within the middleweight class, the relationship between ranking in boxing competition performance and some physiological factors. METHODS: Eight elite Italian amateur boxers (first series of AIBA ranking) were assessed in 2 testing sessions, a week apart. In the first testing session all subjects underwent anthropometric measurements from which body fat percentage, upper arm and forearm muscle cross-sectional areas were estimated. In the second testing session all subjects performed grip strength measures and a maximal treadmill test to assess oxygen consumption (VO2), blood lactate and heart rate at maximal effort, at individual anaerobic threshold, and at individual ventilatory threshold. The athletes were ranked following the criteria of world amateur AIBA ranking. In this ranking the first ranked boxer had the highest score gained participating in international tournaments. RESULTS: A Spearman rho correlation analysis revealed that the VO2 at individual anaerobic threshold (46.0+/-4.2 ml x kg(-1) x min(-1), r=0.91) and the hand-grip strength (58.2+/-6.9 kg, r=0.87) were highly related (p<0.01) to boxing competition ranking. VO(2max) (57.5+/-4.7 ml x kg(-1) x min(-1), r=0.81) and wrist girth (17.6+/-0.6 cm, r=0.78) were moderately (p<0.05) related. CONCLUSIONS: These data suggest that there are two basic factors related to boxing performance: physical fitness as indicated by individual anaerobic threshold and maximal oxygen consumption, and upper-body muscular strength as indicated by hand-grip strength.

Adult↗

PubMed2002

Molecular cloning and characterization of human DDX36 and mouse Ddx36 genes, new members of the DEAD/H box superfamily.

With the strategy of homologue molecular cloning using the sequence of the maleless gene (mle) of Drosophila, the novel homologous human and mouse genes with longer DNA/RNA helicase box (DEAD/DEAH box), named DDX36 and Ddx36 genes, respectively, were cloned as new members of the DEAD/H box superfamily. The predicted protein encoded by human DDX36 gene has a sequence identity of 37% and similarity of 58% with the MLE protein of Drosophila and 91% and 94% with the predicted protein encoded by mouse Ddx36 gene, respectively. Northern blotting of DDX36 shows a single strong signal of 3.8 kb in the hybridization pattern in human testis but no or very weak signal in other tissues. The DDX36 gene is mapped to chromosome 3q25.1-3q25.2, in which 26 exons and 25 introns have been identified. DDX36 and Ddx36 genes may be involved in sex development, spermatogenesis and male reproduction.

Amino Acid Sequence↗

PubMed2006

The F-box protein, Ufo1, maintains genome stability by recruiting the yeast mating switch endonuclease, Ho, for rapid proteasome degradation.

We describe a unique E3, the F-box protein, Ufo1, of yeast. Ufo1 recruits the mating switch endonuclease, Ho, to the SCF complex for ubiquitylation. In addition to the F-box and WD40 protein-protein interaction domains found in all F-box proteins, Ufo1 has a unique domain comprising multiple copies of the ubiquitin-interacting motif. Ufo1 interacts with the UbL-UbA protein, Ddi1, via its UIMs, and this is required for turnover of SCFUfo1 complexes. This is a novel function for an UbL-UbA protein. Deletion of the genomic UFO1UIMs is lethal and our data indicate that Ufo1deltaUIM acts as a dominant negative leading to inhibition of the SCF pathway of substrate degradation and to cell cycle arrest. Furthermore, we found that Ddi1 is required for the final stages of degradation of Ho endonuclease. In the absence of Ddi1, Ho does not form a complex with the 19S RP and is stabilized. Stabilization of Ho leads to perturbation of the cell cycle and to the formation of multi-budded cells. Our experiments uncover a novel role for the ubiquitin-proteasome system in maintenance of genome stability.

Cell Cycle↗

PubMed1991

An Arabidopsis thaliana G-box-binding protein similar to the wheat leucine zipper protein identified as HBP-1.

G-box (CCACGTGG) like sequences are present in a variety of plant promoters and in many cases they have been demonstrated to be required for maximal expression of the corresponding gene. A nuclear protein, GBF, interacts specifically with the G-box motif of several RBCS and CAB promoters. Here we describe the isolation of a cDNA from Arabidopsis thaliana that encodes a protein, designated GBF-1, with DNA binding properties similar to GBF. GBF-1 is characterized by a basic/leucine zipper motif which is strikingly similar to the wheat protein identified as HBP-1. GBF-1 also interacts with an oligonucleotide derived from the wheat histone 3 promoter containing the binding site (hexamer, TGACGT) for HBP-1. This DNA element also contains a G-box-like motif, modification of which results in loss in binding of GBF-1.

Amino Acid Sequence↗

PubMed1995

An Inr-containing sequence flanking the TATA box of the human c-sis (PDGF-B) proto-oncogene promoter functions in cis as a co-activator for its intronic enhancer.

High-level activity of the human PDGF-B promoter in choriocarcinoma cell lines depends upon an atypical, intronic enhancer-like element which does not function with heterologous promoters tested. An extensive series of mutant PDGF-B promoter-driven constructs identified a sequence flanking the TATA box which is required specifically for enhancer-mediated transcription in human choriocarcinoma cell lines. This element, which we here term an enhancer-dependent cis co-activator (EDC) contains an Inr (initiator) consensus sequence upstream of the TATA box which is required, but not sufficient for its function. Requirement for the EDC is cell type-specific, since it was dispensable for enhancer-mediated transcription in a human breast cancer cell line. Although it lies within the region defined, the TATA box itself is not required for EDC function, or for basal promoter function which may derive from a second Inr-like sequence situated at the transcriptional start site. These observations indicate that interactions between some promoter and enhancer elements may be more complex than that generally described for 'classical' enhancer systems and may suggest an additional function for the initiator motif.

Base Sequence↗

PubMed1995

An amphioxus Pax gene, AmphiPax-1, expressed in embryonic endoderm, but not in mesoderm: implications for the evolution of class I paired box genes.

Class I paired box genes are widely distributed through the animal phyla but only fruitfly Pox meso and vertebrate Pax-1 and Pax-9 have been adequately characterized. These vertebrate genes have several developmental functions, but their role in patterning the axial skeleton has received the most attention. Because axial skeletons appear after the origin of the vertebrates, special interest attaches to the possible functions of the precursors of Pax-1 and Pax-9 in the invertebrate ancestor of the vertebrates. As a proxy for this ancestor, we studied amphioxus, which is widely thought to be the closest living invertebrate relative of the vertebrates. A cDNA library from developing amphioxus yielded an unequivocal class I paired box gene, AmphiPax-1, that is 2.5 kb long. The gene encodes a 337 amino acid protein that includes a paired domain in which the amino acids are 92% identical to the paired domain amino acids of mouse and human Pax-1 and Pax-9. In situ hybridization detects AmphiPax-1 expression only in the endoderm of the developing pharynx; within this tissue, expression becomes strikingly down-regulated in regions that will fuse with the overlying ectoderm to form gill slits. No transcripts of AmphiPax-1 ever become detectable in any mesodermal structures. We think it likely that, during animal evolution, class I paired box genes originally functioned in endoderm development and were only later co-opted for other roles in mesoderm development; however, other scenarios cannot be ruled out until homologues of these genes are studied in more invertebrate phyla and in the lower vertebrates.

Amino Acid Sequence↗

PubMed1994

Paired box mutations in familial and sporadic aniridia predicts truncated aniridia proteins.

Aniridia, an autosomal dominant ocular disorder characterized by iris hypoplasia, results from mutations in the PAX6 gene, which encodes paired box and homeobox motifs. In this report we describe five new mutations in the paired box region of the human PAX6 gene that are associated with aniridia. The paired box mutations that we detected were in both familial (three) and sporadic (two) cases. All five mutations predict truncated PAX6 proteins. Our study indicates that early premature translational termination mutations in the PAX6 gene result in haploinsufficiency and generate the aniridia phenotype.

Amino Acid Sequence↗

PubMed1993

TATA-box dependent trans-activation of the human HSP70 promoter by Myb proteins.

The oncogene v-myb and its cellular progenitor c-myb encode nuclear, DNA-binding phosphoproteins that function as transcriptional regulators. Previous studies have demonstrated the existence of two distinct transactivation mechanisms for Myb-inducible promoters. One of these mechanisms, exemplified by the chicken mim-1 promoter, involves specific binding of Myb protein to Myb binding sites located upstream of the transcriptional start site. A second mechanism, exemplified by the human HSP70 promoter, does not require the presence of specific Myb binding sites. Here, we have more closely investigated transactivation of the human HSP70 promoter by Myb proteins. Mutational analysis of the human HSP70 promoter failed to show a correlation between Myb-inducibility and the presence of a particular upstream transcription factor binding site, but instead showed that Myb-inducibility was dependent on the presence of a particular type of TATA-box. This suggests that the TATA-box is involved in transactivation by v-Myb and that only a subset of TATA-boxes confers Myb-inducibility. Activation of the HSP70 promoter is dependent on the presence of most of the carboxy terminal amino acid sequences of v-Myb, including the previously identified acidic transactivation domain and a putative leucine-zipper region. Finally, we show that the HSP70 promoter is activated in a Myb binding site independent fashion not only by v-Myb, but also by chicken c-Myb and chicken B-Myb. These observations raise the possibility that the ability to transactivate in a Myb binding-site independent manner is a common property among Myb proteins. Since chicken B-Myb has been shown previously to be unable to transactivate a Myb binding-site containing promoter, such as the mim-1 promoter (Foos et al., 1992), our results also show that both modes of transactivation are independent of each other.

Animals↗