Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.693894
Title: LARP1, an mRNA binding protein involved in cancer progression & platinum resistance
Author: Abd Latip, Normala
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Abstract:
LARP1 is a novel protein that was first identified in Drosophila where it was shown to be required for embryogenesis, spermatogenesis and cell cycle progression. LARP1 is 'La-related protein' by virtue of its La domain and RRM motif, common to all La proteins. Unlike the other members of LARP family, LARP1 also carries a conserved C terminal domain; the tandem DM15 repeat-containing region which is of unknown function, although it has been proposed to be involved in mRNA binding. LARP1 has been shown previously in our lab to regulate the translation of a subset of mRNAs that encode cytoskeletal proteins, as well as the synthesis of proteins required for invasion such as ?-2 catenin, actin-gamma and matrix metalloprotease 14 (MMP-14). Also, LARP1 has been reported to interact with cytoskeletal proteins such as tubulin, keratins, actin, myosin and the cell-cell junction protein, Zona occludens1 (ZO-1) as well as the actin binding proteins: Plectin, Spectrin, Actinin and Tropomyosin and the actin-capping proteins CapZA and CapZB. In this thesis, LARP1 is demonstrated to exist in complexes with both PABP and eIF4E, colocalise within lamellipodia of the cells, and be required for migration. In histological specimens taken from women with normal cervix (normal), pre-invasive cervical intra-epithelial neoplasia (CIN) and invasive squamous cell cancer (SCC), levels of cytoplasmic LARP1 were shown to be elevated from normal to CIN and from CIN to SCC, suggesting an association between levels of cytoplasmic LARP1 and cancer progression. Morphologically, following LARP1 over-expression, there is loss cell-to-cell contact with scattering of cells away from their original clusters. Cells also acquire a spindle-like appearance, and express characteristic of mesenchymal markers, which suggest LARP1 induces epithelial mesenchymal transition (EMT). LARP1 depletion resensitises a platinum-resistant ovarian carcinoma cell line to cisplatin treatment. In this study, we show that cells with reduced LARP1 have lower expression of Mre11 but have unaltered DNA damage recognition by ?H2AX foci. LARP1 knockdown also alters BRCA2 expression and its subcellular localisation following cisplatin treatment. These findings suggest LARP1 depletion impairs the ability of the cell to efficiently repair cytotoxic DNA damage. In this thesis we show that the RNA-binding protein LARP1 is involved in cell migration, epithelial mesenchymal transition and chemotherapeutic resistance. This supports a role for LARP1 in, cancer progression, and suggests it may act as a promising new therapeutic target in cancer.
Supervisor: Blagden, Sarah ; Gabra, Hani Sponsor: Universiti Teknologi MARA
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.693894  DOI: Not available
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