66 research outputs found
Abstract PR20: A 53BP1 integrates DNA repair and p53-dependent cell fate decisions via distinct mechanisms
No full textAbstract
The tumor suppressor protein 53BP1 was first identified as a p53-interacting protein over two decades ago, however its direct contribution to p53-dependent cellular activities has remained enigmatic. Having reinvestigated the link between 53BP1 and p53, we now show 53BP1 plays an important role in directly stimulating genome-wide p53-dependent gene transactivation and repression events in response to ionizing radiation (IR) and synthetic p53 activation. We have also fine-mapped the domains in 53BP1 that modulate p53 activity and reveal it requires both auto-oligomerization and its tandem-BRCT domain-mediated bivalent interactions with p53 and the ubiquitin-specific protease USP28. Loss of 53BP1 or USP28 catalytic activities results in inefficient p53-dependent cell-cycle checkpoint and exit responses. Mechanistically, we show 53BP1-USP28 cooperation to be essential for stimulating normal p53-promoter element interactions and downstream gene transactivation-associated events, yet dispensable for 53BP1-dependent DSB repair regulation. Collectively, our data indicate a upstream role for 53BP1-USP28 complexes in priming p53's transcriptional potential, providing a mechanistic explanation for 53BP1-p53 cooperation in controlling anti-tumorigenic cell-fate decisions. Moreover, we reveal these activities to be distinct and separable from 53BP1's regulation of DNA double-strand break repair pathway choice, and establish the prime function for the 53BP1 BRCT domain and its interaction partner USP28. Our study therefore defines important and novel functions for 53BP1 in enforcing a vital tumor suppressor pathway that are likely to contribute to tumor suppression. In the meeting we will describe these findings and update on recent progress.
This abstract is also being presented as Poster B04.
Citation Format: Raquel Cuella-Martin, Catarina Oliveira, Helen E. Lockstone, Suzanne Snellenberg, Natalia Grolmusova, J Ross Chapman. A 53BP1 integrates DNA repair and p53-dependent cell fate decisions via distinct mechanisms [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr PR20.</jats:p
Volunteers and mega sporting events : developing a research framework
No full textInterest in all aspects of the politics, financing, planning, management and operation of mega sporting events has been highlighted both by success stories and ongoing problems associated with Olympic Games, Football World Cups and other similar events. There is a growing literature that addresses these and related matters through both case history and comparative analyses. Within the context of mega sporting events, the issue of employment creation is an important motivator for host cities and features high on the political justification agenda for bids to host events. At the same time, the most significant working contribution to major mega events in sports, as in other areas, is provided by the very large numbers of volunteers who undertake tasks across the range of opportunities afforded by such events. Numbers of volunteers between 40,000 and 60,000 have been noted for some recent major events. Relatively little is known about these volunteers at mega sporting events and yet their contribution and wider impact is very significant, both to the events themselves and within the host community. This paper seeks to identify the evident gaps that exist in understanding areas such as what volunteers do at mega sporting events; who they are; what motivates them; how volunteering impacts upon their lives; what associated activities they do surrounding the event in the host city; and the extent to which volunteering is recidivistic. The paper concludes with the presentation of a tentative research framework agenda in order to guide future study of this important area
Exon array data analysis using affymetrix power tools and R statistical software
No full textThe use of microarray technology to measure gene expression on a genome-wide scale has been well established for more than a decade. Methods to process and analyse the vast quantity of expression data generated by a typical microarray experiment are similarly well-established. The Affymetrix Exon 1.0 ST array is a relatively new type of array, which has the capability to assess expression at the individual exon level. This allows a more comprehensive analysis of the transcriptome, and in particular enables the study of alternative splicing, a gene regulation mechanism important in both normal conditions and in diseases. Some aspects of exon array data analysis are shared with those for standard gene expression data but others present new challenges that have required development of novel tools. Here, I will introduce the exon array and present a detailed example tutorial for analysis of data generated using this platform
Exon array data analysis using Affymetrix power tools and R statistical software. Brief Bioinform, [Epub ahead of print
No full textAbstract The use of microarray technology to measure gene expression on a genome-wide scale has been well established for more than a decade. Methods to process and analyse the vast quantity of expression data generated by a typical microarray experiment are similarly well-established. The Affymetrix Exon 1.0 ST array is a relatively new type of array, which has the capability to assess expression at the individual exon level. This allows a more comprehensive analysis of the transcriptome, and in particular enables the study of alternative splicing, a gene regulation mechanism important in both normal conditions and in diseases. Some aspects of exon array data analysis are shared with those for standard gene expression data but others present new challenges that have required development of novel tools. Here, I will introduce the exon array and present a detailed example tutorial for analysis of data generated using this platform
53BP1 integrates DNA repair and p53-dependent cell fate decisions via distinct mechanisms
No full textThe tumor suppressor protein 53BP1, a pivotal regulator of DNA double-strand break (DSB) repair, was first identified as a p53-interacting protein over two decades ago. However, its direct contributions to p53-dependent cellular activities remain undefined. Here, we reveal that 53BP1 stimulates genome-wide p53-dependent gene transactivation and repression events in response to ionizing radiation (IR) and synthetic p53 activation. 53BP1-dependent p53 modulation requires both auto-oligomerization and tandem-BRCT domain-mediated bivalent interactions with p53 and the ubiquitin-specific protease USP28. Loss of these activities results in inefficient p53-dependent cell-cycle checkpoint and exit responses. Furthermore, we demonstrate 53BP1-USP28 cooperation to be essential for normal p53-promoter element interactions and gene transactivation-associated events, yet dispensable for 53BP1-dependent DSB repair regulation. Collectively, our data provide a mechanistic explanation for 53BP1-p53 cooperation in controlling anti-tumorigenic cell-fate decisions and reveal these activities to be distinct and separable from 53BP1’s regulation of DNA double-strand break repair pathway choice
Morris water maze training-induced epigenetic modifications and gene expression changes in rat dentate gyrus neurons
No full textGene expression in the prefrontal cortex during adolescence: implications for the onset of schizophrenia
No full textAbstract Background Many critical maturational processes take place in the human brain during postnatal development. In particular, the prefrontal cortex does not reach maturation until late adolescence and this stage is associated with substantial white matter volume increases. Patients with schizophrenia and other major psychiatric disorders tend to first present with overt symptoms during late adolescence/early adulthood and it has been proposed that this developmental stage represents a "window of vulnerability". Methods In this study we used whole genome microarrays to measure gene expression in post mortem prefrontal cortex tissue from human individuals ranging in age from 0 to 49 years. To identify genes specifically altered in the late adolescent period, we applied a template matching procedure. Genes were identified which showed a significant correlation to a template showing a peak of expression between ages 15 and 25. Results Approximately 2000 genes displayed an expression pattern that was significantly correlated (positively or negatively) with the template. In the majority of cases, these genes in fact reached a plateau during adolescence with only subtle changes thereafter. These include a number of genes previously associated with schizophrenia including the susceptibility gene neuregulin 1 (NRG1). Functional profiling revealed peak expression in late adolescence for genes associated with energy metabolism and protein and lipid synthesis, together with decreases for genes involved in glutamate and neuropeptide signalling and neuronal development/plasticity. Strikingly, eight myelin-related genes previously found decreased in schizophrenia brain tissue showed a peak in their expression levels in late adolescence, while the single myelin gene reported increased in patients with schizophrenia was decreased in late adolescence. Conclusion The observed changes imply that molecular mechanisms critical for adolescent brain development are disturbed in schizophrenia patients.</p
2-D DIGE Analysis of Liver and Red Blood Cells Provides Further Evidence for Oxidative Stress in Schizophrenia
No full textThe molecular disease mechanisms associated with schizophrenia remain largely unknown. Although
primarily considered a disorder of the brain, there is evidence of a peripheral component to
schizophrenia. In this study, we investigated liver tissue and red blood cells (RBC) from schizophrenia
patients and controls using 2-D DIGE proteomic analysis. Fourteen proteins were significantly altered
in liver samples from schizophrenia patients (n = 15) compared to healthy controls (n = 15). Analysis
of the schizophrenia RBC proteome revealed 8 proteins significantly altered in samples from
schizophrenia patients (13 antipsychotic-treated and 7 drug-naïve) compared to controls (n = 20). Six
of the altered proteins in the liver and four of the altered RBC proteins are related to oxidative stress.
These results corroborate our earlier findings obtained from post-mortem brain studies and substantiate
our hypothesis that metabolic alterations leading to oxidative stress are linked to the schizophrenia
disease process. Our results also suggest that at least some of the pathological processes associated
with the schizophrenia disease process can be traced in peripheral tissue. If peripheral cells can be
used as a disease surrogate, promising new investigative avenues could be explored.
Keywords: schizophrenia • oxidative stress • peripheral disease markers • proteomic
2-D DIGE Analysis of Liver and Red Blood Cells Provides Further Evidence for Oxidative Stress in Schizophrenia
No full textThe molecular disease mechanisms associated with schizophrenia remain largely unknown. Although
primarily considered a disorder of the brain, there is evidence of a peripheral component to
schizophrenia. In this study, we investigated liver tissue and red blood cells (RBC) from schizophrenia
patients and controls using 2-D DIGE proteomic analysis. Fourteen proteins were significantly altered
in liver samples from schizophrenia patients (n = 15) compared to healthy controls (n = 15). Analysis
of the schizophrenia RBC proteome revealed 8 proteins significantly altered in samples from
schizophrenia patients (13 antipsychotic-treated and 7 drug-naïve) compared to controls (n = 20). Six
of the altered proteins in the liver and four of the altered RBC proteins are related to oxidative stress.
These results corroborate our earlier findings obtained from post-mortem brain studies and substantiate
our hypothesis that metabolic alterations leading to oxidative stress are linked to the schizophrenia
disease process. Our results also suggest that at least some of the pathological processes associated
with the schizophrenia disease process can be traced in peripheral tissue. If peripheral cells can be
used as a disease surrogate, promising new investigative avenues could be explored.
Keywords: schizophrenia • oxidative stress • peripheral disease markers • proteomic
2-D DIGE Analysis of Liver and Red Blood Cells Provides Further Evidence for Oxidative Stress in Schizophrenia
No full textThe molecular disease mechanisms associated with schizophrenia remain largely unknown. Although
primarily considered a disorder of the brain, there is evidence of a peripheral component to
schizophrenia. In this study, we investigated liver tissue and red blood cells (RBC) from schizophrenia
patients and controls using 2-D DIGE proteomic analysis. Fourteen proteins were significantly altered
in liver samples from schizophrenia patients (n = 15) compared to healthy controls (n = 15). Analysis
of the schizophrenia RBC proteome revealed 8 proteins significantly altered in samples from
schizophrenia patients (13 antipsychotic-treated and 7 drug-naïve) compared to controls (n = 20). Six
of the altered proteins in the liver and four of the altered RBC proteins are related to oxidative stress.
These results corroborate our earlier findings obtained from post-mortem brain studies and substantiate
our hypothesis that metabolic alterations leading to oxidative stress are linked to the schizophrenia
disease process. Our results also suggest that at least some of the pathological processes associated
with the schizophrenia disease process can be traced in peripheral tissue. If peripheral cells can be
used as a disease surrogate, promising new investigative avenues could be explored.
Keywords: schizophrenia • oxidative stress • peripheral disease markers • proteomic
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