3,686 research outputs found
Dissecting Mechanisms of Transformation Following Loss of p53 and RB
No full textAbstractFor over 30 years the cancer biology field has scrutinized the mechanisms behind p53 and RB mediated tumor suppression (Fields and Jang 1990; Kern et al. 1991; Raycroft, Wu, and Lozano 1990; Dyson 1998; Classon and Harlow 2002; Knudsen and Knudsen 2008) Together, these genes regulate complex interconnecting pathways responsible for the regulation of cell growth, cell death, and genomic integrity (Sherr and McCormick 2002). Not surprisingly, the pathways regulated by these two tumor suppressors are almost universally disrupted during the development of cancer (Hanahan and Weinberg 2000).
By nature, tumor suppressors play a key role in preserving the integrity of the genome. Whether in response to injury or in maintaining stable gene expression patterns, p53 and RB have been well established as two of the most important factors preventing genomic instability, epigenetic deregulation, transformation, and tumorigenesis. However, the precise mechanism by which p53 or RB mediate tumor suppression remains unclear (Tiwari, Jones, and Abrams 2018). Over the last decade, several studies in genetically engineered mouse models have demonstrated that the canonical functions of these two tumor suppressors fail to fully explain their tumor suppressive capabilities (Mello and Attardi 2018; Janic et al. 2018; T. Li et al. 2012). Moreover, expanding literature continues to highlight a strong correlation between transposable element de-repression and several types of cancer, however, no definitive link between transposable elements and tumorigenesis has been established (Tiwari, Jones, and Abrams 2018; Wylie et al. 2016; Tiwari et al. 2020; Rodriguez-Martin et al. 2020). At present, the role that genomic repetitive elements play in tumorigenesis remains an open question. Here, to elucidate a possible mechanism of transformation we sought to investigate the link between the concurrent loss of p53 and RB and the de-repression of transposons. While individually, p53 and RB have been implicated in separate transposable element defense mechanisms, each responsible for preventing the expression of transposons (Ishak et al. 2016; Wylie et al. 2016; Tiwari et al. 2020; Dick et al. 2018; Tiwari, Jones, and Abrams 2018), my thesis work seeks to understand the role these repetitive elements play in transformation. Specifically, I investigate how the combined loss of p53 and RB affect the expression of transposons and how this relates to the development of cancer.
Using genetically engineered mouse models we derived several lines of mouse embryonic fibroblasts (MEFs) which, through cre-lox technology, allowed for the deletion of floxed tumor suppressors (H. Kim et al. 2018). We derived MEFs from mice containing floxed p53, RB, both p53 and RB as well as several p53 and RB mutants. Generating primary MEFs allowed us to interrogate the loss of p53 and RB in a non-cancerous context, free of additional mutations (Todaro and Green 1963; Xu 2005). Moreover, by choosing MEFs as a model system, we could harness and observe the transformation process in a minimally manipulated system. Accordingly, we transformed normal Wild Type (WT) MEF cells and induced transformation by recombining loxP sites flanking p53 and RB. In dissecting whether loss of p53 and RB affected transposable element expression we showed that loss of p53 or RB alone each partially derepress long interspersed nuclear element 1 (LINE1) transposable elements, but remarkably co-deletion of p53 and RB together not only transform cells but also simultaneously induce massive expression of LINE1. Additionally, through the use of p53 transactivation domain mutants, we showed that the ability of p53 to repress transposable elements is a non-canonical function linked to tumor suppression. Interrogation of short interspersed nuclear elements (SINEs) produced similar findings. Furthermore, the derepression of both LINEs and SINEs appears to be regulated by the modification of the H3K9me3 histone mark. These results further correlate the expression of transposable elements to transformation and tumorigenesis.
Complementary work revealed that loss of both p53 and RB in MEFs not only derepressed transposable elements and transformed cells, but in the process, massively rearranged the three-dimensional (3-D) chromatin landscape. This change in 3-D chromatin architecture resulted in the loss of intrachromosomal loops and the subsequent overexpression of several oncogenes. To assess the scope of the rearrangement of chromatin architecture, we developed a UCSC genome browser based atlas, mapping thousands DNA loops stemming from promoters, enhancers and silencers. We find that while the general structure of topologically associated domains are largely stable (Dixon et al. 2012), following deletion of p53 or RB, local chromatin contacts are vastly reorganized. Moreover, the reorganization of DNA loops was found to affect gene expression in a context dependent manner. These results support a model of p53 and RB as guardians of the genome that cooperate to maintain the chromatin architecture required for normal cellular function and prevent changes in DNA topology that promote uncontrolled growth associated with cellular transformation.
More than half of all cancer patients have mutations in p53 or RB and many harbor evidence of deregulated transposable elements amidst a disordered chromatin landscape. Here, we explore the distinct and overlapping genomic regulatory processes that p53 and RB cooperatively maintain to preserve genomic integrity and prevent cancer. Overall, my work implicates transposable element derepression as a mechanism that can promote the development of cancer and moreover, provides a genome wide atlas of how p53 and RB can affect the chromatin landscape to regulate gene expression in a context dependent manner. Moreover, my work provides mechanistic insight into the tissue specific functions of p53 and RB. Taken together, this thesis provides new insights into the mechanisms by which p53 and RB prevent cancer.
</p
Liquid structure of Rb-Hg alloys studied by neutron diffraction
No full textThe structures of liquid Rb–Hg alloys were studied as a function of composition by neutron diffraction. In the intermediate Rb concentration range, the obtained structure factors show a small prepeak, which may be an evidence of the formation of Hg polyanion units in liquids. The Reverse Monte Carlo (RMC) analysis was applied to separate the total radial distribution function into the corresponding partial radial distribution functions. Up to 10 at.% Rb, no obvious changes are found for the first peak position of the partial radial distribution functions of the Hg–Hg pair and that of the Hg–Rb pair. The first peak position between the Hg–Rb pairs increases above 20 at.% Rb. In addition to the first peak, a subpeak between Hg–Hg pairs can be seen in the large distance. At 60 at.% Rb, the nearest neighbor distance between Hg atoms shows the closest value in the concentration range studied. These results indicate that with the progress of charge transfer the solvation structure in the dilute Rb concentration range changes into the structure containing polyanions composed of Hg species
Fractional Edge Cover Number of Model RB
No full textModel RB is a random constraint satisfaction problem with a growing domain size, which exhibits exact phase transition phenomena. Many hard instances with planted solutions can be generated via Model RB, to be used as benchmarks for algorithmic competitions and researches. In the past, some structural parameters of constraint hypergraphs are analyzed to show hardness of Model RB, such as hinge width, decycling number, treewidth, and hypertree width. In this paper, one more structural parameter of constraint hypergraphs of Model RB, namely the fractional edge cover number, is analyzed. We show upper and lower bounds on the fractional edge cover number of Model RB. In particular, the fractional edge cover number of Model RB is shown to be asymptotically linear in the number of variables, like hinge width, decycling number, treewidth and hypertree width. These results together provide further evidences on the hardness of Model RB.EICPCI-S(ISTP)[email protected]
Pulmonary inflammation associated with aspirated meconium and epithelial-cells in calves
No full text"Meconium aspiration syndrome" is a condition resulting in respiratory distress and the occasional death of newborn human beings. A retrospective study was conducted on 52 calves that were submitted for postmortem examination to the Atlantic Veterinary College, Charlottetown, Prince Edward Island, Canada. These calves died of infectious and noninfectious diseases within the first 2 weeks of life due to a variety of causes. The most common cause of death was infectious enteric disease. Histologic examination of lungs revealed that 42.5% of calves had evidence of meconium, squamous cells, or keratin in the lung. There was considerable variation in the magnitude of histologic changes in lungs containing aspirated material. Typically, affected lungs had only a few inconspicuous pieces of meconium, keratin, and squamous cells within bronchoalveolar spaces. Sporadically, the entire lumen of airways was obliterated by aspirated material. Lungs with aspirated material had a mild but diffuse alveolitis characterized by exudation of a few neutrophils, macrophages, and occasional multinucleated giant cells. Obstruction of small airways and focal atelectasis were also observed. Similar lesions have been reported in human meconium aspiration syndrome. It is concluded that histologic changes similar to those of human meconium aspiration syndrome occur commonly in calves that die within 2 weeks of birth. Further studies involving healthy age-matched calves are required to evaluate the clinico-pathologic significance of meconium aspiration in this species.PT: J; CR: BESSER TE, 1990, J AM VET MED ASSOC, V196, P1239 BLOCK MF, 1981, OBSTET GYNECOL, V57, P37 BLOOD DC, 1989, VET MED TXB DISEASES, P95 BOYD JW, 1989, BRIT VET J, V145, P249 BRADY JP, 1986, NEONATAL PULMONARY C, P483 BRYAN CS, 1967, J HOPKINS MED J, V121, P9 CARSON BS, 1976, AM J OBSTET GYNECOL, V126, P712 CLARK DA, 1987, J PEDIATR, V110, P765 CRUICKSHANK AH, 1949, J PATHOL BACTERIOL, V61, P527 DAVIS RO, 1985, AM J OBSTET GYNECOL, V151, P731 DAWES GS, 1985, PULMONARY DEV TRANSI, P75 DOOLEY SL, 1985, AM J OBSTET GYNECOL, V153, P767 DUBIELZIG RR, 1977, EQUINE MED SURGERY, V1, P419 DUENHOELTER JH, 1976, AM J OBSTET GYNECOL, V125, P306 DUNGWORTH DL, 1985, PATHOLOGY DOMESTIC A, V2, P413 GOODING CA, 1971, PEDIATR RADIOL, V100, P137 GREGORY GA, 1974, J PEDIATR, V85, P848 JANSSEN W, 1984, FORENSIC HISTOPATHOL, P135 KREBS HB, 1980, AM J OBSTET GYNECOL, V137, P936 LOPEZ A, 1984, CAN J COMP MED, V48, P275 LOPEZ A, 1989, CAN VET J, V30, P519 LUNA LG, 1968, MANUAL HIST STAINING, P82 MARTIN SW, 1987, VET EPIDEMIOLOGY PRI, P128 MILLER RB, 1977, CAN VET J, V18, P87 MITSUDO SM, 1983, J PEDIATR, V103, P598 MRISON JE, 1963, FOETAL NEONATAL PATH, P450 MURPHY JD, 1984, J PEDIATR, V104, P758 MURRAY JF, 1986, NORMAL LUNG, P1 ROSSI EM, 1989, AM J OBSTET GYNECOL, V161, P1106 SPENCER H, 1985, PATHOLOGY LUNG, V1, P527 SWAMINATHAN S, 1989, J PEDIATR, V114, P356 SZENCI O, 1989, THERIOGENOLOGY, V31, P667 TING P, 1975, AM J OBSTET GYNECOL, V122, P767 TYLER DC, 1978, PEDIATRICS, V62, P454 VIDYASAGAR D, 1982, APPLIED PHYSL CLIN R, P401 VYAS H, 1986, TXB NEONATOLOGY, P317 WARNER AE, 1988, LAB INVEST, V59, P219; NR: 37; TC: 17; J9: VET PATHOL; PG: 8; GA: HG847Source type: Electronic(1
MILLIMETER-WAVE SPECTROSCOPY OF COLD RB ATOMS
No full textAuthor Institution: Department of Physics, University of Virginia, McCormick Road, Charlottesville, Virginia 22903Cold Rb atoms were prepared by magneto-optical trap. Millimeter-wave has been used to drive nd to (n-2)f one-photon and nd to (n-1)g () two-photon transitions. Quantum defects of f and g states of Rb were calculated. Full analyses will be presented. }
Interpretation and the Problem of the Intention of the Author, by Burhanetir Tatar
No full textBurhanetir Tatar, Interpretation and the Problem of the Intention of the Author: H.G. Gadamer vs E.D. Hirsh, The Council for Research in Values and Philosophy, 199
Abstract 1988: Exosome-mediated ovarian cancer tumorigenesis mediated by miR1246/Rb/Cav1 axis
No full textAbstract
Exosomes are secreted from many cell types and play an important role in the tumor microenvironment. The most impressive breakthrough in exosomes research was that they contain the genetic material of the host cell. However, whether cancer cells use their exosomes to transfer their oncogenic material to recipient cells, or to get rid of their tumor suppressor material is not well understood. We previously identified that miR-1246 was hundreds of folds higher expressed in six different ovarian cancer exosomes compared to their originating cells. Here, we showed that miR-1246 co-localized in the exosomes in ovarian cancer cells. miR-1246 act as an oncogenic miRNA and the levels were elevated in ovarian cancer patients compared to health donors. We also demonstrated that miR-1246 inhibitor treatment in combination with paclitaxel was significantly inhibited tumor burden in SKOV3-ip1 orthotopic ovarian cancer model. Our results suggest that miR-1246 inhibited RB tumor suppressor protein and regulate Cav-1 and platelet-derived growth factor receptor beta precursor signaling in ovarian cancer. In addition Inhibiting miR-1246 led a significant decrease in exosome release. Together, our findings provide strong evidence that oncogenic miR-1246 can be targeted as a potential novel therapeutic approach in the treatment of ovarian cancer.
.
Note: This abstract was not presented at the meeting.
Citation Format: Pinar Kanlikilicer, Recep Bayraktar, Mohammed Rashed, Burcu Aslan, George A. Calin, Anil K. Sood, Gabriel Lopez-Berestein. Exosome-mediated ovarian cancer tumorigenesis mediated by miR1246/Rb/Cav1 axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1988. doi:10.1158/1538-7445.AM2017-1988</jats:p
Aneuploidy in spermatids of Robertsonian (Rb) chromosome heterozygous mice
No full text© 2014, The Author(s). Rb translocations are chromosomal rearrangements frequently found in natural populations of the house mouse Mus musculus domesticus. The standard diploid karyotype of the house mouse consisting of 40 telocentric chromosomes may be reduced by the emergence of metacentric Rb chromosomes. Multiple simple Rb heterozygotes form trivalents exhibiting higher anaphase nondisjunction frequency and consequently higher number of unbalanced gametes than in normal males. This work will attempt to establish whether frequencies of aneuploidy observed in heterozygote spermatids of the house mouse M. musculus domesticus show differences in chromosomes derived from different trivalents. Towards this goal, the number and distribution frequency of aneuploidy was assessed via FISH staining of specific chromosomes of spermatids derived from 2n = 32 individuals. Our results showed that for a given set of target chromosomes, 90 % of the gametes were balanced, resulting from alternate s
Synthesis and Characterization of Multiple-Cation Rb(MAFA)PbI3 Perovskite Single Crystals
No full textWe synthesized multiple-cation Rb(MAFA)PbI3 perovskite single crystals for the first time. The effect of Rb+ substitution was systemically investigated, and the addition of 1.5 M 5% RbI was the optimum condition to obtain high-quality Rb(MAFA)PbI3 single crystals. Lattice shrinkage occurred in the Rb(MAFA)PbI3 single crystal because of the small ionic radius of Rb+, resulting in blue-shifted absorption and photoluminescence (PL) peaks. The 1.5 M 5% RbI-added (MAFA)PbI3 single crystal showed the longest carrier lifetime of 18.35 ns, exhibiting the highest photoresponse than other crystals. We believe that this work will provide a basic insight into the mixed-cation perovskite single crystals for the future optoelectronic applications. © The Author(s) 201
TEMPERATURE DEPENDENCE OF AND (n=3-5) CLUSTER IONS
No full textAuthor Institution: Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801Competition between ionwater electrostatic interactions and waterwater hydrogen bonding allows several structural isomers of hydrated rubidium cluster ions to exist simultaneously. The cluster ion temperature plays a large role in determining which of these non-covalent interactions will dominate. Colder temperatures favor isomers with multiple hydrogen bonds while warmer temperatures favor less-structured isomers with fewer hydrogen bonds. The temperature, or internal energy, of hydrated rubidium cluster ions is controlled by varying the evaporative path available for cluster formation. If the evaporation involves loss of water molecules, the final cluster ion temperature will be in the range of . Evaporation of argon atoms generates substantially colder cluster ions with temperatures of . Infrared photodissociation spectra of are compared with \textit{(n=3-5)} spectra to illustrate entropic effects on the relative abundance of structural isomers in clusters. The identification of isomers present is aided by parallel \textit{ab initio}, RRKM-EE and thermodynamics calculations
- …
