501 Matching Results

Search Results

Advanced search parameters have been applied.

Ovarian carcinomas with genetic and epigenetic BRCA1 loss havedistinct molecular abnormalities

Description: Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.
Date: July 23, 2007
Creator: Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda et al.
Partner: UNT Libraries Government Documents Department

Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

Description: Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n=5), clear cell (n=4), or low grade serous (n=2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.
Date: May 2, 2008
Creator: Gilks, C. Blake; Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle et al.
Partner: UNT Libraries Government Documents Department

Versatile P(acman) BAC Libraries for Transgenesis Studies in Drosophila melanogaster

Description: We constructed Drosophila melanogaster BAC libraries with 21-kb and 83-kb inserts in the P(acman) system. Clones representing 12-fold coverage and encompassing more than 95percent of annotated genes were mapped onto the reference genome. These clones can be integrated into predetermined attP sites in the genome using Phi C31 integrase to rescue mutations. They can be modified through recombineering, for example to incorporate protein tags and assess expression patterns.
Date: April 21, 2009
Creator: Venken, Koen J.T.; Carlson, Joseph W.; Schulze, Karen L.; Pan, Hongling; He, Yuchun; Spokony, Rebecca et al.
Partner: UNT Libraries Government Documents Department

Induction of Visible Mutations in Mormoniella by Use of Low Frequency Ultrasonic Energy

Description: Low-frequency ultrasonic energy was utilized in an attempt to induce visible mutations in the parasitoid wasp Mormoniella vitripennis. This study demonstrates that low frequency ultrasound may be used as an effective mutagenic agent in this organism, and suggests that it may have applications to other genetic systems.
Date: August 1972
Creator: Grubbs, Steven C.
Partner: UNT Libraries

Site Directed Mutagenesis Of Dienelactone Hydrolase

Description: The role of individual amino acid residues of the enzyme dienelactone hydrolase was investigated. Using the polymerase chain reaction (PCR), a 1.9 kbp clcD fragment was amplified and subcloned yielding a 821 bp BamHI to EcoRI clcD subclone in the plasmid pUC19. Site-specific mutants of dienelactone hydrolase were created using mismatched oligonucleotides to prime DNA synthesis. Specifically modified proteins from mutated clcD genes (Arg 81 to alanine, Tyr 85 to phenylalanine and Arg 206 to alanine), were encoded by the mutant clones. Enzyme assays showed that dienelactone hydrolase activity of the mutants Arg 81 and Arg 206 was totally abolished. The DLHase enzyme activity of mutant Tyr 85 is greatly decreased by approximately two thirds.
Date: December 1992
Creator: Chen, Wei, 1965-
Partner: UNT Libraries

Hereditary Spherocytosis and Hereditary Elliptocytosis: Aberrant Protein Sorting during Erythroblast Enucleation

Description: During erythroblast enucleation, membrane proteins distribute between extruded nuclei and reticulocytes. In hereditary spherocytosis (HS) and hereditary elliptocytosis (HE), deficiencies of membrane proteins, in addition to those encoded by the mutant gene, occur. Elliptocytes, resulting from protein 4.1R gene mutations, lack not only 4.1R but also glycophorin C, which links the cytoskeleton and bilayer. In HS resulting from ankyrin-1 mutations, band 3, Rh-associated antigen, and glycophorin A are deficient. The current study was undertaken to explore whether aberrant protein sorting, during enucleation, creates these membrane-spanning protein deficiencies. We found that although glycophorin C sorts to reticulocytes normally, it distributes to nuclei in 4.1R-deficient HE cells. Further, glycophorin A and Rh-associated antigen, which normally partition predominantly to reticulocytes, distribute to both nuclei and reticulocytes in an ankyrin-1-deficient murine model of HS. We conclude that aberrant protein sorting is one mechanistic basis for protein deficiencies in HE and HS.
Date: February 8, 2010
Creator: Salomao, Marcela; Chen, Ke; Villalobos, Jonathan; Mohandas, Narla; An, Xiuli & Chasis, Joel Anne
Partner: UNT Libraries Government Documents Department

Wasted (wst) mice have 3-bp deletion in the PCNA promoter

Description: Mice homozygous for the autosomal recessive wasted mutation (wst/wst) have abnormalities in T-lymphocytes and in the anterior motor neuron cells of the spinal cord, leading to sensitivity to ionizing radiation, hind limb paralysis, and immunodeficiency. This defect results in a failure to gain weight by 20 days and death at 28 days of age. Previous results from the authors` group have shown that (1) wasted mice have little if any detectable PCNA protein or mRNA in thymus, but levels in liver, brain, and other tissues are similar to those in controls; and (2) the coding region for PCNA is the same in wasted mice and in control littermates. These observations gave rise to the present study, in which the PCNA promoter was sequenced for wst/wst mice, control littermates ({center_dot}wst/+) and BCF{sub 1} (or BALB/c x C57BL/6) F{sub 1} controls. Sequence analysis revealed only one difference between wst/wst and BALB/c x C57BL/6 F{sub 1} littermates: a 3-bp deletion in the 5 foot upstream region of the PCNA gene of wasted mice that was observed on only one allele or no alleles of normal littermates. The mutated sites in PCNA promoter from two litters plus two additional wst/wst and two known wst/+ animals were screened with 8G and 11G probes, and each confirmed this pattern. The short term DNA segment encompassing the deletion was shown in gel shift experiments to bind a nuclear protein(s) present in a broad variety of cells including thymus and spleen nuclear extract from wst/wst and control mice. The mutated oligomer that was homozygous only in wst/wst mice was not able to bind the same nuclear protein(s).
Date: August 1, 1997
Creator: Paunesku, T. & Woloschak, G.E.
Partner: UNT Libraries Government Documents Department

A Maximum Entropy Formalism for Disentangling Chains of Correlated Sequence Positions

Description: Covariation analysis of sets of aligned sequences of protein molecules is successful in certain instances in elucidating certain structural and functional links, but in general, pairs of sites displaying highly covarying mutations in protein sequences do not necessarily correspond to sites that are spatially close in the protein structure. In contrast, covariation analysis of sets of aligned sequences for RNA molecules is relatively successful in elucidating RNA secondary structure, as well as some aspects of tertiary structure. The goals of this paper are to (1) present the problem, (2) develop the mathematical formalism for solving the problem, and (3) validate the resulting algorithms on simulated data. Extensive application to biological sequences will be presented elsewhere.
Date: August 3, 1998
Creator: Lapedes, A.S.; Giraud, B.G.; Liu, L.C. & Stormo, G.D.
Partner: UNT Libraries Government Documents Department

Intrasplicing coordinates alternative first exons with alternative splicing in the protein 4.1R gene

Description: In the protein 4.1R gene, alternative first exons splice differentially to alternative 3' splice sites far downstream in exon 2'/2 (E2'/2). We describe a novel intrasplicing mechanism by which exon 1A (E1A) splices exclusively to the distal E2'/2 acceptor via two nested splicing reactions regulated by novel properties of exon 1B (E1B). E1B behaves as an exon in the first step, using its consensus 5' donor to splice to the proximal E2'/2 acceptor. A long region of downstream intron is excised, juxtaposing E1B with E2'/2 to generate a new composite acceptor containing the E1B branchpoint/pyrimidine tract and E2 distal 3' AG-dinucleotide. Next, the upstream E1A splices over E1B to this distal acceptor, excising the remaining intron plus E1B and E2' to form mature E1A/E2 product. We mapped branch points for both intrasplicing reactions and demonstrated that mutation of the E1B 5' splice site or branchpoint abrogates intrasplicing. In the 4.1R gene, intrasplicing ultimately determines N-terminal protein structure and function. More generally, intrasplicing represents a new mechanism whereby alternative promoters can be coordinated with downstream alternative splicing.
Date: November 7, 2008
Creator: Conboy, John G.; Parra, Marilyn K.; Tan, Jeff S.; Mohandas, Narla & Conboy, John G.
Partner: UNT Libraries Government Documents Department

CHROMOSOMAL ABERRATIONS IN A NATURAL POPULATION OF CHIRONOMUS TENTANS EXPOSED TO CHRONIC LOW-LEVEL ENVIRONMENTAL RADIATION

Description: The salivary gland chromosomes of Chironomus tentans larvae collected from White Oak Creek, an area contaminated by radioactive waste from the Oak Ridge National Laboratory, and from six uncontaminated areas were examined for chromosomal aberrations. White Oak Creek populations were exposed to absorbed doses as high as 230 rads per year or about 1000 times background. Chromosomal maps were constructed to make a general comparison of the banding pattern of the salivary chromosomes of the C. tentans in the East Tennessee area with those of Canada and Europe. These maps were used as a reference in scoring aberrations. Fifteen different chromosomal aberrations were found in 365 larvae taken from the irradiated population as compared with five different aberrations observed in 356 larvae from six control populations, but the mean number of aberrations per larva did not differ in any of the populations. The quantitative amount of heterozygosity was essentially the same in the irradiated and the control population, but there were three times the variety of chromosomal aberrations found in the irradiated area. From this evidence it was concluded that chronic low-level irradiation from radioactive waste was increasing the variability of chromosomal aberrations without significantly increasing the frequency. It was also concluded that chromosomal polymorphism can be maintained in a natural population without superiority of the heterozygous individuals. (C.H.)
Date: January 29, 1964
Creator: Blaylock, B G; Auerbach, S I & Nelson, D J
Partner: UNT Libraries Government Documents Department

Overexpressed of RAD51 suppresses recombination defects: a possible mechanism to reverse genomic instability

Description: RAD51, a key protein in the homologous recombinational DNA repair (HRR) pathway, is the major strand-transferase required for mitotic recombination. An important early step in HRR is the formation of single-stranded DNA (ss-DNA) coated by RPA (a ss-DNA binding protein). Displacement of RPA by RAD51 is highly regulated and facilitated by a number of different proteins known as the 'recombination mediators'. To assist these recombination mediators, a second group of proteins also is required and we are defining these proteins here as 'recombination co-mediators'. Defects in either recombination mediators or comediators, including BRCA1 and BRCA2, lead to impaired HRR that can genetically be complemented for (i.e. suppressed) by overexpression of RAD51. Defects in HRR have long been known to contribute to genomic instability leading to tumor development. Since genomic instability also slows cell growth, precancerous cells presumably require genomic restabilization to gain a growth advantage. RAD51 is overexpressed in many tumors, and therefore, we hypothesize that the complementing ability of elevated levels of RAD51 in tumors with initial HRR defects limits genomic instability during carcinogenic progression. Of particular interest, this model may also help explain the high frequency of TP53 mutations in human cancers, since wild-type p53 represses RAD51.
Date: October 15, 2009
Creator: Schild, David & Wiese, Claudia
Partner: UNT Libraries Government Documents Department

Final technical report, August 15, 1971--August 14, 1972

Description: Work to date on mutations of the incompatibility factors and other genes affecting their expression in Schizophylium commune is briefly summarized. A second line of research, biochemical consequences of development in Schizophyllum, is also briefly reported. Four separate papers have been published to date on work under the contract. (LMT)
Date: January 1, 1972
Creator: Raper, J R & Hoffman, R M
Partner: UNT Libraries Government Documents Department

Of extracellular matrix, scaffolds, and signaling: Tissuearchitectureregulates development, homeostasis, and cancer

Description: The microenvironment surrounding cells influences gene expression, such that a cell's behavior is largely determined by its interactions with the extracellular matrix, neighboring cells, and soluble cues released locally or by distant tissues. We describe the essential role of context and organ structure in directing mammary gland development and differentiated function, and in determining response to oncogenic insults including mutations. We expand on the concept of 'dynamic reciprocity' to present an integrated view of development, cancer, and aging, and posit that genes are like piano keys: while essential, it is the context that makes the music.
Date: March 9, 2006
Creator: Nelson, Celeste M. & Bissell, Mina J.
Partner: UNT Libraries Government Documents Department

Generating Molecular Biology Tools to Investigate the Ca2+ Binding Ability of Arabidopsis TON2

Description: The position of the cell division plane in plants is determined by the position of the preprophase band. The pre prophase band (PPB) is a ring of microtubules centered around the nucleus on the inner side of plasma membrane that establishes the cortical division site. The PPB forms at the end of G2 and breaks down at the end of prophase leaving behind protein markers of its position that are collectively called the cortical division site. During cytokinesis the phragmoplast expands towards the cortical division site and mediates the fusion of the new cell plate with the mother cell at that position. Several proteins necessary for PPB formation in plants have been identified, including maize DCD1 and ADD1 and Arabidopsis TON2, which are all type 2A protein phosphatase (PP2A)B" regulatory subunits. DCD1, ADD1, and TON2 localize to the PPB and the cortical division site through metaphase. The PP2A subunits each have two EF-hand domains, which are predicted to bind calcium ions. Since calcium ions are important for some aspects of cell division, we designed a series of constructs to test if TON2 binds calcium. TON2 protein was cloned into expression vectors, pET42a, and expression of TON2 protein was confirmed via Western blotting and immunodetection using a GST antibody. Site directed mutagenesis was used to mutate the TON2 EF-hand domains and mutated cDNAs were also cloned into expression vectors. These were then expressed in bacterial systems. Finally, the GST tagged proteins were purified. In the future, wild-type and mutated proteins TON2 proteins will used in calcium binding assays to determine if TON2 binds calcium.
Date: August 2017
Creator: Shao, Danyang
Partner: UNT Libraries

The Evolutionary Dynamics of Cancer

Description: We hypothesized that a subset of the mutations observed in the progression to cancer confer beneficial selective effects on the cell. Our aim was to identify these selective mutations and to infer the interactions between the mutant clones in Barrett's esophagus (BE) that eventually lead to the development of esophageal adenocarcinoma. The results were to be a set of predictions about the roles of specific mutations in the progression to cancer.
Date: August 29, 2000
Creator: Maley, Carlo C.
Partner: UNT Libraries Government Documents Department

Modified cellulose synthase gene from 'Arabidopsis thaliana' confers herbicide resistance to plants

Description: Cellulose synthase ('CS'), a key enzyme in the biosynthesis of cellulose in plants is inhibited by herbicides comprising thiazolidinones such as 5-tert-butyl-carbamoyloxy-3-(3-trifluromethyl) phenyl-4-thiazolidinone (TZ), isoxaben and 2,6-dichlorobenzonitrile (DCB). Two mutant genes encoding isoxaben and TZ-resistant cellulose synthase have been isolated from isoxaben and TZ-resistant Arabidopsis thaliana mutants. When compared with the gene coding for isoxaben or TZ-sensitive cellulose synthase, one of the resistant CS genes contains a point mutation, wherein glycine residue 998 is replaced by an aspartic acid. The other resistant mutation is due to a threonine to isoleucine change at amino acid residue 942. The mutant CS gene can be used to impart herbicide resistance to a plant; thereby permitting the utilization of the herbicide as a single application at a concentration which ensures the complete or substantially complete killing of weeds, while leaving the transgenic crop plant essentially undamaged.
Date: October 11, 2000
Creator: Somerville, Chris R. & Scieble, Wolf
Partner: UNT Libraries Government Documents Department