Publication:
Roles of activation transcription factor 4 (ATF4) and YrdC in the response of vascular smooth muscle cells to injury

dc.contributor.advisor Khachigian, Levon Michael en_US
dc.contributor.advisor Chesterman, Colin en_US
dc.contributor.author Malabanan, Kristine Paz en_US
dc.date.accessioned 2022-03-22T14:50:51Z
dc.date.available 2022-03-22T14:50:51Z
dc.date.issued 2008 en_US
dc.description.abstract Neointimal proliferation is a key process underlying many cardiovascular diseases such as atherosclerosis and angioplasty-induced restenosis. Vascular smooth muscle cells (SMC) are significant contributors to the development and stability of the neointimal lesion. This is due, in part, to their capacity to be phenotypically modulated, facilitating SMC proliferation in response to mechanical injury, their subsequent migration, and deposition of extracellular matrix. The aim of this thesis was to characterize the function of two genes identified in our laboratory to be upregulated shortly after mechanical injury of vascular SMC and their exposure to fibroblast growth factor (FGF)-2, an injury-induced cytokine. The first is activation transcription factor (ATF) 4, which is upregulated by FGF-2 and mechanical injury in vascular SMC in vitro, and by balloon-injury in the artery wall. The induction of ATF4 by FGF-2 was shown to be mediated through the PI3K pathway, and preceded by phoshorylation of eIF2alpha, a known upstream effector of ATF4 activation. Knock-down of ATF4 expression inhibited balloon-injury induced neointimal hyperplasia, suggesting that ATF4 is a key player in the SMC response to injury. Furthermore, microarray analysis identified several genes whose transcription in response to FGF-2 may be regulated by ATF4. In particular, this work demonstrates that ATF4 is necessary for VEGF-A upregulation in SMC in response to FGF-2 and mechanical injury in vitro and in the artery wall following balloon-injury. The second is a translation factor, YrdC203. Using confocal fluorescence microscopy, YrdC203 was found to localize partially to the ER, and with RPL12, a component of the 60S ribosomal subunit. Immunoprecipitation studies demonstrate that YrdC203 also interacts with an initiation factor, eIF5B. Mutation of an initiation factor’s signature on the exterior of YrdC203 perturbed its interaction with RPL12 and eIF5B, and inhibited the increase in protein synthesis observed with overexpression of YrdC203. This implicates YrdC203 as a translation factor responsible for ensuring protein synthesis in vascular SMC in response to injury. The present work provides evidence for new molecular mechanisms, transcriptional and translational, regulating the response of vascular SMC to injury. This would provide leads for future therapeutic targets. en_US
dc.identifier.uri http://hdl.handle.net/1959.4/41338
dc.language English
dc.language.iso EN en_US
dc.publisher UNSW, Sydney en_US
dc.rights CC BY-NC-ND 3.0 en_US
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/3.0/au/ en_US
dc.subject.other YrdC en_US
dc.subject.other vascular smooth muscle cell injury en_US
dc.subject.other ATF4 en_US
dc.title Roles of activation transcription factor 4 (ATF4) and YrdC in the response of vascular smooth muscle cells to injury en_US
dc.type Thesis en_US
dcterms.accessRights open access
dcterms.rightsHolder Malabanan, Kristine Paz
dspace.entity.type Publication en_US
unsw.accessRights.uri https://purl.org/coar/access_right/c_abf2
unsw.identifier.doi https://doi.org/10.26190/unsworks/19646
unsw.relation.faculty Medicine & Health
unsw.relation.originalPublicationAffiliation Malabanan, Kristine Paz, Centre for Vascular Research, Faculty of Medicine, UNSW en_US
unsw.relation.originalPublicationAffiliation Khachigian, Levon Michael, Centre for Vascular Research, Faculty of Medicine, UNSW en_US
unsw.relation.originalPublicationAffiliation Chesterman, Colin, Centre for Vascular Research, Faculty of Medicine, UNSW en_US
unsw.relation.school School of Medical Sciences *
unsw.thesis.degreetype PhD Doctorate en_US
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