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dc.contributor.supervisor Wigle, Jeffrey (Biochemistry and Medical Genetics) en_US
dc.contributor.author Northcott, Josette M. D.
dc.date.accessioned 2012-11-13T16:44:46Z
dc.date.available 2012-11-13T16:44:46Z
dc.date.issued 2007-01 en_US
dc.date.issued 2011-12-10 en_US
dc.identifier.citation Douville JM, Wigle JT. Regulation and function of homeodomain proteins in the embryonic and adult vascular systems. Can J Physiol Pharmacol. 2007 Jan;85(1):55-65. Review. PubMed PMID: 17487245 en_US
dc.identifier.citation Douville JM, Cheung DY, Herbert KL, Moffatt T, Wigle JT. Mechanisms of MEOX1 and MEOX2 regulation of the cyclin dependent kinase inhibitors p21 and p16 in vascular endothelial cells. PLoS One. 2011;6(12):e29099. Epub 2011 Dec 20. PubMed PMID: 22206000 en_US
dc.identifier.uri http://hdl.handle.net/1993/11243
dc.description.abstract The mesenchyme homeobox genes, MEOX1 and MEOX2, encode homeodomain transcription factors. Studies of Meox1/Meox2 knockout mice established that these proteins are partially redundant during development, suggesting that they may regulate common target genes. In the adult vasculature, MEOX2 is expressed in vascular smooth muscle and endothelial cells. MEOX2 has been demonstrated to: i) inhibit proliferation, ii) activate apoptosis and iii) induce senescence. In contrast, the role of MEOX1 has not been studied in the vasculature. Currently, there are two known target genes of MEOX2: cyclin-dependent kinase inhibitor 1A (CDKN1A/p21CIP1/WAF1) and cyclin-dependent kinase inhibitor 2A (CDKN2A/p16INK4a), which regulate transient (quiescent) and permanent (senescent) cell cycle arrest. Senescence is postulated to contribute to the development of atherosclerotic vascular disease by promoting endothelial dysfunction. We hypothesized that MEOX1 and MEOX2 would activate both p21CIP1/WAF1 and p16INK4a expression, as well as induce apoptosis, cell cycle arrest and senescence in endothelial cells. Furthermore, we postulated that the majority of newly identified MEOX target genes in endothelial cells would be regulated by both MEOX1 and MEOX2. MEOX proteins were expressed in human endothelial cells via adenoviral transduction. Levels of target gene expression were measured by luciferase reporter gene assays, western blot and quantitative real-time PCR. Electrophoretic mobility shift assays were used to demonstrate MEOX binding to DNA. Cellular proliferation, senescence, and apoptosis were evaluated. For the identification of novel target genes, microarrays were used to compare levels of gene expression in endothelial cells transduced with MEOX constructs or control virus. Both MEOX1 and MEOX2 activated p21CIP1/WAF1 and p16INK4a gene transcription, inhibited proliferation and induced apoptosis and senescence in endothelial cells. MEOX activation of p21CIP1/WAF1 transcription occurs via a DNA-binding independent mechanism that requires the SP1 transcription factor. In contrast, MEOX activation of p16INK4a transcription is dependent upon DNA-binding. Microarray analysis revealed that both MEOX1 and MEOX2 increased the expression of intercellular adhesion molecule 1 (ICAM-1) and decreased the expression of nitric oxide synthase 3 (NOS3/eNOS). Taken together, we conclude that MEOX1 and MEOX2 have similar target genes in endothelial cells including p21CIP1/WAF1, p16INK4a and eNOS. As increased endothelial senescence and decreased nitric oxide production are hallmarks of endothelial dysfunction, this study proposes a role for the MEOX proteins in the progression of atherosclerotic vascular disease. en_US
dc.publisher NRC Research Press en_US
dc.publisher PLoS One en_US
dc.subject endothelial cells en_US
dc.subject homeodomain proteins en_US
dc.title The role of the mesenchyme homeobox genes in the regulation of vascular endothelial cell function en_US
dc.degree.discipline Biochemistry and Medical Genetics en_US
dc.contributor.examiningcommittee Triggs-Raine, Barbara (Biochemistry and Medical Genetics) Davie, James (Biochemistry and Medical Genetics) Czubryt, Michael (Physiology) Srivastava, Ashok (University of Montreal) en_US
dc.degree.level Doctor of Philosophy (Ph.D.) en_US
dc.description.note February 2013 en_US


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