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D Haque

Publications and source records attributed to D Haque.

13 recordsLinked to original sources
PubMed1999

The elongin B ubiquitin homology domain. Identification of Elongin B sequences important for interaction with Elongin C.

Mammalian Elongin B is a 118-amino acid protein composed of an 84-amino acid amino-terminal ubiquitin-like domain and a 34-amino acid carboxyl-terminal tail. Elongin B is found in cells as a subunit of the heterodimeric Elongin BC complex, which was originally identified as a positive regulator of RNA polymerase II elongation factor Elongin A and subsequently as a component of the multiprotein von Hippel-Lindau tumor suppressor and suppressor of cytokine signaling complexes. As part of our effort to understand how the Elongin BC complex regulates the activity of Elongin A, we are characterizing Elongin B functional domains. In this report, we show that the Elongin B ubiquitin-like domain is necessary and sufficient for interaction with Elongin C and for positive regulation of Elongin A transcriptional activity. In addition, by site-directed mutagenesis of the Elongin B ubiquitin-like domain, we identify a short Elongin B region that is important for its interaction with Elongin C. Finally, we observe that both the ubiquitin-like domain and carboxyl-terminal tail are conserved in Drosophila melanogaster and Caenorhabditis elegans Elongin B homologs that efficiently substitute for mammalian Elongin B in reconstitution of the transcriptionally active Elongin ABC complex, suggesting that the carboxyl-terminal tail performs an additional function not detected in our assays.

Amino Acid Sequence↗
PubMed1998

The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families.

The Elongin BC complex was identified initially as a positive regulator of RNA polymerase II (Pol II) elongation factor Elongin A and subsequently as a component of the multiprotein von Hippel-Lindau (VHL) tumor suppressor complex, in which it participates in both tumor suppression and negative regulation of hypoxia-inducible genes. Elongin B is a ubiquitin-like protein, and Elongin C is a Skp1-like protein that binds to a BC-box motif that is present in both Elongin A and VHL and is distinct from the conserved F-box motif recognized by Skp1. In this report, we demonstrate that the Elongin BC complex also binds to a functional BC box present in the SOCS box, a sequence motif identified recently in the suppressor of cytokine signaling-1 (SOCS-1) protein, as well as in a collection of additional proteins belonging to the SOCS, ras, WD-40 repeat, SPRY domain, and ankyrin repeat families. In addition, we present evidence (1) that the Elongin BC complex is a component of a multiprotein SOCS-1 complex that attenuates Jak/STAT signaling by binding to Jak2 and inhibiting Jak2 kinase, and (2) that by interacting with the SOCS box, the Elongin BC complex can increase expression of the SOCS-1 protein by inhibiting its degradation. These results suggest that Elongin BC is a multifunctional regulatory complex capable of controlling multiple pathways in the cell through interaction with a short degenerate sequence motif found in many different proteins.

Amino Acid Sequence↗
PubMed1998

Genotypic differences between C57BL/6 and A inbred mice in anxiolytic and sedative actions of diazepam.

The role of genotype in susceptibility to the behavioral actions of benzodiazepines is not well characterized. To develop a model for such studies, we have characterized the anxiolytic and sedative activities of diazepam in C57BL/6J and A/J inbred mice. C57BL/6J mice were more responsive than A/J mice to diazepam-induced anxiolytic-like activity in the mirrored chamber aversion assay and the elevated plus-maze assay. Basal activity of the two strains did not differ in either assay. In contrast, the two strains were equally responsive to the anxiolytic effects of the 5-HT1A receptor partial agonist, buspirone. C57BL/6J mice were also more susceptible to the sedative effects of diazepam than were A/J mice. Flumazenil blocked the effects of diazepam in these behavioral assays. Measurement of diazepam and nordiazepam in blood and brain suggested that the response differences are of a pharmacodynamic rather than a pharmacokinetic nature. Taken together, these findings indicate that C57BL/6J and A/J mice provide a valuable tool for behavioral genetic studies of the mechanisms underlying the pharmacological actions of benzodiazepines.

Animals↗
PubMed1998

Use of ultrasound-guided fine needle aspiration biopsy in the management of thyroid disease.

Fine-needle aspiration biopsy (FNAB) of thyroid nodules has resulted in fewer patients needing thyroidectomy. Nondiagnostic FNAB specimens may require surgery for diagnosis. Ultrasound can help decrease nondiagnostic biopsies by visualizing lesions and guiding biopsy needles. Between 1996 and 1997, 76 patients had ultrasound-guided needle biopsies of thyroid nodules. Sixteen patients had clearly palpable nodules, whereas 19 were described as difficult to palpate. There were 32 patients who presented with either prominent thyroids or enlarged lobes. Six patients presented only with nonspecific symptoms, and 3 had nodules discovered incidentally on imaging studies. Biopsies were diagnostic in 73 of 76 (96%) patients. This varied with the size of the nodule, with the rate of nondiagnostic biopsies being 13 per cent in lesions <1.0 cm and 3 per cent in lesions >2.0 cm. Fifteen patients had surgery based on the FNAB, with a surgical yield of malignancy of 47 per cent. Ultrasound-guided FNAB is extremely useful in evaluating thyroid lesions that are difficult to palpate or nonpalpable, as well as the remainder of the gland and surrounding structures. The use of ultrasound guidance in performing FNAB results in a low rate of nondiagnostic biopsies, which may decrease the number of unnecessary thyroidectomies performed to rule out malignancy.

Biopsy, Needle↗
PubMed1997

Structure and function of RNA polymerase II elongation factor ELL. Identification of two overlapping ELL functional domains that govern its interaction with polymerase and the ternary elongation complex.

The human ELL gene on chromosome 19p13.1 undergoes frequent translocations with the trithorax-like MLL gene on chromosome 11q23 in acute myeloid leukemia. Recently, the human ELL gene was shown to encode an RNA polymerase II elongation factor that activates elongation by suppressing transient pausing by polymerase at many sites along the DNA. In this report, we identify and characterize two overlapping ELL functional domains that govern its interaction with RNA polymerase II and the ternary elongation complex. Our findings reveal that, in addition to its elongation activation domain, ELL contains a novel type of RNA polymerase II interaction domain that is capable of negatively regulating polymerase activity in promoter-specific transcription initiation in vitro. Notably, the MLL-ELL translocation results in deletion of a portion of this functional domain, and ELL mutants lacking sequences deleted by the translocation bind RNA polymerase II and are fully active in elongation, but fail to inhibit initiation. Taken together, these results raise the possibility that the MLL-ELL translocation could alter ELL-RNA polymerase II interactions that are not involved in regulation of elongation.

Chromosomes, Human, Pair 19↗
PubMed1997

ELL2, a new member of an ELL family of RNA polymerase II elongation factors.

We recently isolated an RNA polymerase II elongation factor from rat liver nuclei and found it to be homologous to the product of the human ELL gene, a frequent target for translocations in acute myeloid leukemia. To further our understanding of the possible role(s) of ELL in transcriptional regulation and human disease, we initiated a search for ELL-related proteins. In this report we describe molecular cloning, expression, and characterization of human ELL2, a novel RNA polymerase II elongation factor 49% identical and 66% similar to ELL. Mechanistic studies indicate that ELL2 and ELL possess similar transcriptional activities. Structure-function studies localize the ELL2 elongation activation domain to an ELL2 N-terminal region that is highly homologous to ELL. Finally, Northern blot analysis reveals that the ELL2 and ELL genes are transcribed in many of the same tissues, but that the ratio of their transcripts exhibits tissue-to-tissue variation, raising the possibility that ELL2 and ELL may not perform completely general functions, but, instead, may perform gene- or tissue-specific functions.

Amino Acid Sequence↗
PubMed1997

The GABAA receptor alpha 6 subunit gene (Gabra6) is tightly linked to the alpha 1-gamma 2 subunit cluster on mouse chromosome 11.

We have established that the GABAA receptor alpha 6 (Gabra6) and alpha 1 (Gabra 1) subunit genes are tightly linked on mouse chromosome 11 by analysing the strain distribution patterns of RFLPs for the two genes and microsatellite markers flanking these genes in 26 BXD recombinant inbred strains. These results further demonstrate clustering of the GABAA receptor subunit genes on mouse chromosomes and the synteny for these clusters between the mouse and human genomes.

Animals↗
PubMed1996

The inducible elongin A elongation activation domain: structure, function and interaction with the elongin BC complex.

The elongin (SIII) complex strongly stimulates the rate of elongation by RNA polymerase II by suppressing transient pausing by polymerase at many sites along the DNA. Elongin (SIII) is composed of a transcriptionally active A subunit and two small regulatory B and C subunits, which bind stably to each other to form a binary complex that interacts with elongin A and strongly induces its transcriptional activity. The elongin (SIII) complex is a potential target for negative regulation by the von Hippel-Lindau (VHL) tumor suppressor protein, which is capable of binding stably to the elongin BC complex and preventing it from activating elongin A. Here, we identify an elongin A domain sufficient for activation of elongation and demonstrate that it is a novel type of inducible activator that targets the RNA polymerase II elongation complex and is evolutionarily conserved in species as distantly related as Caenorhabditis elegans and man. In addition, we demonstrate that both the elongin A elongation activation domain and the VHL tumor suppressor protein interact with the elongin BC complex through a conserved elongin BC binding site motif that is essential for induction of elongin A activity by elongin BC and for tumor suppression by the VHL protein.

Amino Acid Sequence↗
PubMed1996

A human cDNA encoding the 110-kDa A subunit of RNA polymerase II transcription factor elongin.

A full-length cDNA encoding a human homolog of the approx. 110-kDa subunit (elongin A; El A) of the RNA polymerase II transcription factor, elongin, was isolated and sequenced. Comparison of the open reading frames of the human el A cDNA and the previously characterized rat El A cDNA [Aso et al., Science 269 (1995) 1439-1443] indicates that they are 84% conserved in nucleotide sequence and encode 84% identical proteins.

Amino Acid Sequence↗
PubMed1994

A human cDNA encoding the small subunit of RNA polymerase II transcription factor SIII.

A full-length cDNA encoding a human homolog of the 15-kDa subunit (p15) of RNA polymerase II elongation factor SIII was isolated and sequenced. Comparison of the open reading frames of the human p15 cDNA and the previously characterized rat p15 cDNA [Garrett et al., Proc. Natl. Acad. Sci. USA 91 (1994) 5237-5241] indicates that they encode identical proteins and are 93% conserved in nucleotide sequence.

Amino Acid Sequence↗
PubMed1988

Correlation between sperm morphology, acrosin, and fertilization in an IVF program.

Acrosin, a neutral proteinase, is located within the acrosome. The aim of this study was to evaluate acrosin concentrations in patients with severe damage of the sperm head and to determine whether acrosin concentration could predict the chances of fertilization in an IVF program. Sixty patients were accepted into this study, prospectively. The patients were divided into two groups, those with a normal morphology of less than 14% (group I, n = 33) and those with normal morphology less than 14% (group II, n = 27). All patients had a sperm concentration of less than 20 million sperm/ml and less than 30% progressively motile sperm. The acrosin assays were performed on the semen sample obtained on the day of IVF. Routine IVF insemination procedures were used, and only mature oocytes were considered. The only factor that showed a significant correlation of fertilization was normal morphology (p less that 0.01). The mean acrosin level was 73.4 /+- 38.6 mED/10 million sperm in group I and 70.9 /+- 42.7 mIU/10 million sperm in group II (no significant difference). The fertilization rate in group I was 45.4% and in group II, 77.7% p less than 0.002). Acrosin levels were not significantly different in patients with and without fertilization (72.0 /+- 42.1 and 73.6 /+- mIU/10 million sperm, respectively).

Acrosin↗