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1. p53 and responses to DNA damage in small airway epithelium

Author

Armit, Christopher James

Subjects
616.2
Abstract

The effects of p53 were investigated in a mouse model of acute lung injury and in short-term primary cultures of isolated Clara cells. Gene targeted mice, germline deficient in p53, were exposed to γ-irradiation and compared to wild type controls. The in vivo response was to DNA damage was characterised in terms of growth arrest, apoptosis, morphology, and gene expression. An acute stress response was observed in vivo, and localised to a subpopulation of the lung epithelium, the bronchiolar cells. p53 was stabilised in this population and was associated with transcriptional induction of Bax, but not other bcl-2 family members. p53 deficient mice did not display this rapid accumulation of Bax transcripts, as assessed by RNase Protection Assay. Within wild type and p53 null mice, γ-irradiation did not induce apoptosis in lung epithelial cells at any timepoints studied, as assessed by morphology, but induce strand breaks that were detectable by TUNEL. Cell cycle activity as assessed by BrdU incorporation, was infrequent in the lung at all timepoints, regardless of p53 status, and hence an effect of p53 on cell cycle progression was not detected in vivo. The effects of p53-deficiency was additionally investigated in short-term primary cultures of murine bronchiolar Clara cells. Culturing of Clara cells allowed an assessment of the functional consequences of p53 deficiency in proliferating cells. Clara cells, isolated from gene-targeted p53-deficient mice, were compared to cells derived from wild type littermates. Baseline proliferation rates, as determined by BrdU incorporation, were similar irrespective of p53 status. p53 null cultures displayed abnormal morphology; specifically, a high incidence of multinucleation, which increased with time in culture. Multinucleated cells maintained expression of the Clara cell marker for CC10, and were proficient in S phase DNA synthesis, as determined by BrdU incorporation. Nucleation defects in p53 -/- Clara cells associated with abnormalities in mitosis and cytokinesis, as documented by time-lapse videomicroscopy, and with increased centrosome number, determined by confocal microscopy.

Published
2001

2. Alteplase for Acute Ischemic Stroke: Outcomes by Clinically Important Subgroups in the Third International Stroke Trial

Author

Lindley, Richard I., Wardlaw, Joanna M., Whiteley, William N., Cohen, Geoff, Blackwell, Lisa, Murray, Gordon D., Sandercock, Peter A.G., Baigent, Colin, Professor, Chadwick, David, Professor, Tyrrell, Pippa, Dr, Lowe, Gordon, Professor, Dennis, Martin, Professor, Innes, Karen, Ms, Goodare, Heather, Farrall, Andrew, von Kummer, Rüdiger, Cala, Lesley, von Heijne, Anders, Morris, Zoe, Adami, Alessandro, Peeters, Andre, Potter, Gillian, Brady, Nick, Collins, Rory, Professor, Bath, Philip, Professor, van Gijn, Jan, Professor, Gray, Richard, Professor, Hart, Robert, Professor, Yusuf, Salim, Professor, Muir, Keith, Hankey, Graeme J., Matz, Karl, Brainin, Michael, Peters, Andre, Gubitz, Gord, Phillips, Stephen, Ricci, Stefano, Arauz, Antonio, Berge, Eivind, Bruins Slot, Karsten, Czlonkowska, Anna, Kobayashi, Adam, Correia, Manuel, Lyrer, Phillippe, Engelter, Stefan, Murray, Veronica, Norrving, Bo, Terént, Andreas, Wester, Per, Venables, Graham, Innes, Karen, Clark, Alison, Perry, David, Soosay, Vera, Buchanan, David, Grant, Sheila, Sakka, Eleni, Drever, Jonathan, Walker, Pauli, Herath, Indee, Brown, Ann Leigh, Chmielnik, Paul, Armit, Christopher, Walton, Andrea, Hautvast, Mischa, Lewis, Steff, Heron, Graeme, Odusanya, Sylvia, Linksted, Pam, Kane, Ingrid, Sellar, Robin, White, Philip, Keston, Peter, Farrell, Andrew, Morris, Zoe, Miranda, Hector, Celani, Maria Grazia, Righetti, Enrico, Cenciarelli, Silvia, Mazzoli, Tatiana, Cantisani, Teresa Anna, Bembenek, Jan, and Isaakson, Eva

Published
2015
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3. Absence of p53 in Clara cells favours multinucleation and loss of cell cycle arrest

Author

Clarke Alan R, O'Dea Shirley, Armit Christopher J, and Harrison David J

Subjects
Cytology, QH573-671
Abstract

Abstract Background The p53 oncosuppressor protein is a critical mediator of the response to injury in mammalian cells and is mutationally inactivated in the majority of lung malignancies. In this analysis, the effects of p53-deficiency were investigated in short-term primary cultures of murine bronchiolar Clara cells. Clara cells, isolated from gene-targeted p53-deficient mice, were compared to cells derived from wild type littermates. Results p53 null cultures displayed abnormal morphology; specifically, a high incidence of multinucleation, which increased with time in culture. Multinucleated cells were proficient in S phase DNA synthesis, as determined by BrdU incorporation. However, multinucleation did not reflect altered rates of S phase synthesis, which were similar between wild type and p53-/- cultures. Nucleation defects in p53-/- Clara cells associated with increased centrosome number, as determined by confocal microscopy of pericentrin-stained cultures, and may highlight a novel role of p53 in preserving genomic integrity in lung epithelial cells. Effects of p53-deficiency were also studied following exposure to DNA damage. A p53-dependent reduction in the BrdU index was observed in Clara cells following ionizing radiation. The reduction in BrdU index in wild type cells displayed serum-dependency, and occurred only in the absence of serum. Taken together, these findings demonstrate that in murine primary Clara cell culture, cell cycle arrest is a p53-mediated response to DNA damage, and that extracellular factors, such as serum, influence this response. Conclusion These findings highlight functions of wild type p53 protein in bipolar spindle formation, centrosome regulation, and growth control in bronchiolar Clara cells.

Published
2002
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4. eMouseAtlas Informatics:Embryo Atlas and Gene Expression

Author

Armit, Christopher, Richardson, Lorna, Hill, Bill, Yang, Yiya, and Baldock, Richard

Abstract

A significant proportion of developmental biology data is presented in the form of images at morphologically diverse stages of development. The curation of these datasets presents different challenges to that of sequence/text-based data. Towards this end, the eMouseAtlas project created a digital atlas of mouse embryo development as a means of understanding developmental anatomy and exploring the relationship between genes and development in a spatial context. Using the morphological staging system pioneered by Karl Theiler, the project has generated 3D models of post-implantation mouse development and used them as a spatial framework for the delineation of anatomical components and for archiving in situ gene expression data in the EMAGE database. This has allowed us to develop a unique online resource for mouse developmental biology. We describe here the underlying structure of the resource, as well as some of the tools that have been developed to allow users to mine the curated image data. These tools include our IIP3D/X3DOM viewer that allows 3D visualisation of anatomy and/or gene expression in the context of a web browser, and the eHistology resource that extends this functionality to allow visualisation of high-resolution cellular level images of histology sections. Furthermore, we review some of the informatics aspects of eMouseAtlas to provide a deeper insight into the use of the atlas and gene expression database.

Published
2015
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5. Absence of p53 in Clara cells favours multinucleation and loss of cell cycle arrest

Author

Armit, Christopher, O'Dea, Shirley, Clarke, Alan Richard, and Harrison, David John

Subjects
respiratory system, QR
Abstract

Background\ud \ud The p53 oncosuppressor protein is a critical mediator of the response to injury in mammalian cells and is mutationally inactivated in the majority of lung malignancies. In this analysis, the effects of p53-deficiency were investigated in short-term primary cultures of murine bronchiolar Clara cells. Clara cells, isolated from gene-targeted p53-deficient mice, were compared to cells derived from wild type littermates.\ud Results\ud \ud p53 null cultures displayed abnormal morphology; specifically, a high incidence of multinucleation, which increased with time in culture. Multinucleated cells were proficient in S phase DNA synthesis, as determined by BrdU incorporation. However, multinucleation did not reflect altered rates of S phase synthesis, which were similar between wild type and p53-/- cultures. Nucleation defects in p53-/- Clara cells associated with increased centrosome number, as determined by confocal microscopy of pericentrin-stained cultures, and may highlight a novel role of p53 in preserving genomic integrity in lung epithelial cells. Effects of p53-deficiency were also studied following exposure to DNA damage. A p53-dependent reduction in the BrdU index was observed in Clara cells following ionizing radiation. The reduction in BrdU index in wild type cells displayed serum-dependency, and occurred only in the absence of serum. Taken together, these findings demonstrate that in murine primary Clara cell culture, cell cycle arrest is a p53-mediated response to DNA damage, and that extracellular factors, such as serum, influence this response.\ud Conclusion\ud \ud These findings highlight functions of wild type p53 protein in bipolar spindle formation, centrosome regulation, and growth control in bronchiolar Clara cells.

Published
2002

6. Absence of p53 in Clara cells favours multinucleation and loss of cell cycle arrest

Author

Armit, Christopher J., O'Dea, Shirley, Clarke, Alan R., Harrison, David J., Armit, Christopher J., O'Dea, Shirley, Clarke, Alan R., and Harrison, David J.

Abstract

Background The p53 oncosuppressor protein is a critical mediator of the response to injury in mammalian cells and is mutationally inactivated in the majority of lung malignancies. In this analysis, the effects of p53-deficiency were investigated in short-term primary cultures of murine bronchiolar Clara cells. Clara cells, isolated from gene-targeted p53-deficient mice, were compared to cells derived from wild type littermates. Results p53 null cultures displayed abnormal morphology; specifically, a high incidence of multinucleation, which increased with time in culture. Multinucleated cells were proficient in S phase DNA synthesis, as determined by BrdU incorporation. However, multinucleation did not reflect altered rates of S phase synthesis, which were similar between wild type and p53-/- cultures. Nucleation defects in p53-/- Clara cells associated with increased centrosome number, as determined by confocal microscopy of pericentrin-stained cultures, and may highlight a novel role of p53 in preserving genomic integrity in lung epithelial cells. Effects of p53-deficiency were also studied following exposure to DNA damage. A p53-dependent reduction in the BrdU index was observed in Clara cells following ionizing radiation. The reduction in BrdU index in wild type cells displayed serum-dependency, and occurred only in the absence of serum. Taken together, these findings demonstrate that in murine primary Clara cell culture, cell cycle arrest is a p53-mediated response to DNA damage, and that extracellular factors, such as serum, influence this response. Conclusion These findings highlight functions of wild type p53 protein in bipolar spindle formation, centrosome regulation, and growth control in bronchiolar Clara cells.

Published
2002

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