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RISS 인기검색어
- 검색키워드
- 저자 : Jessica L. Bell (검색결과 2 건)
- 무료
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Predisposition to Cancer Caused by Genetic and Functional Defects of Mammalian <i>Atad5</i>
Bell, Daphne W.,Sikdar, Nilabja,Lee, Kyoo-young,Price, Jessica C.,Chatterjee, Raghunath,Park, Hee-Dong,Fox, Jennifer,Ishiai, Masamichi,Rudd, Meghan L.,Pollock, Lana M.,Fogoros, Sarah K.,Mohamed, Hassa Public Library of Science 2011 PLoS genetics Vol.7 No.8
<▼1><P>ATAD5, the human ortholog of yeast Elg1, plays a role in PCNA deubiquitination. Since PCNA modification is important to regulate DNA damage bypass, ATAD5 may be important for suppression of genomic instability in mammals <I>in vivo</I>. To test this hypothesis, we generated heterozygous (<I>Atad5<SUP>+/m</SUP></I>) mice that were haploinsuffficient for Atad5. <I>Atad5<SUP>+/m</SUP></I> mice displayed high levels of genomic instability <I>in vivo</I>, and <I>Atad5<SUP>+/m</SUP></I> mouse embryonic fibroblasts (MEFs) exhibited molecular defects in PCNA deubiquitination in response to DNA damage, as well as DNA damage hypersensitivity and high levels of genomic instability, apoptosis, and aneuploidy. Importantly, 90% of haploinsufficient <I>Atad5<SUP>+/m</SUP></I> mice developed tumors, including sarcomas, carcinomas, and adenocarcinomas, between 11 and 20 months of age. High levels of genomic alterations were evident in tumors that arose in the <I>Atad5<SUP>+/m</SUP></I> mice. Consistent with a role for <I>Atad5</I> in suppressing tumorigenesis, we also identified somatic mutations of <I>ATAD5</I> in 4.6% of sporadic human endometrial tumors, including two nonsense mutations that resulted in loss of proper ATAD5 function. Taken together, our findings indicate that loss-of-function mutations in mammalian <I>Atad5</I> are sufficient to cause genomic instability and tumorigenesis.</P></▼1><▼2><P><B>Author Summary</B></P><P>Genomic instability is a hallmark of tumorigenesis, suggesting that mutations in genes suppressing genomic instability contribute to this phenotype. In this study, we demonstrate for the first time that haploinsufficiency for Atad5, a protein that is important in stabilizing stalled DNA replication forks by regulating PCNA ubiquitination during DNA damage bypass, predisposes >90% of mice to tumorigenesis in multiple organs. In heterozygous <I>Atad5</I> mice, both somatic cells and the spontaneous tumors showed high levels of genomic instability. In a subset of sporadic human endometrial tumors, we identified heterozygous loss-of-function somatic mutations in the <I>ATAD5</I> gene, consistent with the role of mouse <I>Atad5</I> in suppressing tumorigenesis. Collectively, our findings suggest that <I>ATAD5</I> may be a novel tumor suppressor gene.</P></▼2>
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In vivo tumour imaging employing regional delivery of novel Gallium radiolabelled polymer composites
Ross W. Stephens,Gregory D. Tredwell,Jessica L. Bell,Karen J. Knox,Lee A. Philip,Tim J. Senden,Michael J. Tapner,Stephanie A. Bickley,Marcel R. Tanudji,Stephen K. Jones 한국생체재료학회 2021 생체재료학회지 Vol.25 No.2
Background: Understanding the regional vascular delivery of particles to tumour sites is a prerequisite for developing new diagnostic and therapeutic composites for treatment of oncology patients. We describe a novel imageable 67Ga-radiolabelled polymer composite that is biocompatible in an animal tumour model and can be used for preclinical imaging investigations of the transit of different sized particles through arterial networks of normal and tumour-bearing organs. Results: Radiolabelling of polymer microspheres with 67Ga was achieved using a simple mix and wash method, with tannic acid as an immobilising agent. Final in vitro binding yields after autoclaving averaged 94.7%. In vivo stability of the composite was demonstrated in New Zealand white rabbits by intravenous administration, and intrahepatic artery instillations were made in normal and VX2 tumour implanted rabbit livers. Stability of radiolabel was sufficient for rabbit lung and liver imaging over at least 3 hours and 1 hour respectively, with lung retention of radiolabel over 91%, and retention in both normal and VX2 implanted livers of over 95%. SPECT-CT imaging of anaesthetised animals and planar imaging of excised livers showed visible accumulation of radiolabel in tumours. Importantly, microsphere administration and complete liver dispersal was more easily achieved with 8 μm diameter MS than with 30 μm MS, and the smaller microspheres provided more distinct and localised tumour imaging. Conclusion: This method of producing 67Ga-radiolabelled polymer microspheres is suitable for SPECT-CT imaging of the regional vascular delivery of microspheres to tumour sites in animal models. Sharper distinction of model tumours from normal liver was obtained with smaller MS, and tumour resolution may be further improved by the use of 68Ga instead of 67Ga, to enable PET imaging.
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