Function of the PDLIM2 protein in oncogenic Wnt signalling pathways

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dc.contributor.advisor O'Connor, Rosemary en Bustamante- Garrido, Milán F. 2016-09-05T09:14:19Z 2016 2016
dc.identifier.citation Bustamante- Garrido, M. F. 2016. Function of the PDLIM2 protein in oncogenic Wnt signalling pathways. PhD Thesis, University College Cork. en
dc.description.abstract Aberrant regulation of the Wnt signalling pathway is a recurrent theme in cancer biology. Hyper activation due to oncogenic mutations and paracrine activity has been found in both colon cancer and breast cancer, and continues to evolve as a central mechanism in oncogenesis. PDLIM2, a cytoskeletal PDZ protein, is an IGF-1 regulated gene that is highly expressed in cancer cell lines derived from metastatic tumours. Suppression of PDLIM2 inhibits polarized cell migration, reverses the Epithelial to Mesenchymal transition (EMT) phenotype, suppresses the transcription of β-catenin target genes, and regulates gene expression of key transcription factors in EMT. This thesis investigates the mechanism by which PDLIM2 contributes to the maintenance of Wnt signalling in cancer cells. Here we show that PDLIM2 is a critical regulator of the Wnt pathway by regulating β-catenin at the adherens juctions, as also its transcriptional activity by the interaction of PDLIM2 with TCF4 at the nucleus. Evaluation of PDLIM2 in macrophages and co-culture studies with cancer cells and fibroblasts showed the influence exerted on PDLIM2 by paracrine cues. Thus, PDLIM2 integrates cytoskeleton signalling with gene expression by modulating the Wnt signalling pathway and reconciling microenvironmental cues with signals in epithelial cells. Negative correlation of mRNA and protein levels in the triple negative breast cancer cell BT549 suggests that PDLIM2 is part of a more complex mechanism that involves transcription and posttranslational modifications. GST pulldown studies and subsequent mass spectrometry analysis showed that PDLIM2 interacts with 300 proteins, with a high biological function in protein biosynthesis and Ubiquitin/proteasome pathways, including 13 E3 ligases. Overall, these data suggest that PDLIM2 has two distinct functions depending of its location. Located at the cytoplasm mediates cytoskeletal re-arrangements, whereas at the nucleus PDLIM2 acts as a signal transduction adaptor protein mediating transcription and ubiquitination of key transcription factors in cancer development. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2016, Milán F. Bustamante- Garrido. en
dc.rights.uri en
dc.subject Epithelial to mesenchymal transition en
dc.subject Wnt signalling en
dc.subject Paracrine activity en
dc.subject Cancer biology en
dc.title Function of the PDLIM2 protein in oncogenic Wnt signalling pathways en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral Degree (Structured) en
dc.type.qualificationname PhD Scholars Programme in Cancer Biology en
dc.internal.availability Full text not available en Indefinite en 10000-01-01
dc.description.version Accepted Version
dc.contributor.funder Health Research Board en
dc.description.status Not peer reviewed en Biochemistry en
dc.check.reason This thesis is due for publication or the author is actively seeking to publish this material en
dc.check.opt-out Yes en
dc.thesis.opt-out true
dc.check.entireThesis Entire Thesis Restricted
dc.check.embargoformat E-thesis on CORA only en
dc.internal.conferring Autumn 2016 en

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© 2016, Milán F. Bustamante- Garrido. Except where otherwise noted, this item's license is described as © 2016, Milán F. Bustamante- Garrido.
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