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Westminsterresearch ZFP36 Proteins and Mrna Targets in B Cell WestminsterResearch http://www.westminster.ac.uk/westminsterresearch ZFP36 proteins and mRNA targets in B cell malignancies Alcaraz, A. This is an electronic version of a PhD thesis awarded by the University of Westminster. © Miss Amor Alcaraz, 2015. The WestminsterResearch online digital archive at the University of Westminster aims to make the research output of the University available to a wider audience. Copyright and Moral Rights remain with the authors and/or copyright owners. Whilst further distribution of specific materials from within this archive is forbidden, you may freely distribute the URL of WestminsterResearch: ((http://westminsterresearch.wmin.ac.uk/). In case of abuse or copyright appearing without permission e-mail [email protected] ZFP36 proteins and mRNA targets in B cell malignancies Maria del Amor Alcaraz-Serrano A Thesis submitted in partial fulfilment of the requirements of the University of Westminster for the degree of Doctor of Philosophy September 2015 Abstract The ZFP36 proteins are a family of post-transcriptional regulator proteins that bind to adenine uridine rich elements (AREs) in 3’ untranslated (3’UTR) regions of mRNAs. The members of the human family, ZFP36L1, ZFP36L2 and ZFP36 are able to degrade mRNAs of important cell regulators that include cytokines, cell signalling proteins and transcriptional factors. This project investigated two proposed targets for the protein family that have important roles in B cell biology, BCL2 and CD38 mRNAs. BCL2 is an anti-apoptotic protein with key roles in cell survival and carcinogenesis; CD38 is a membrane protein differentially expressed in B cells and with a prognostic value in B chronic lymphocytic leukaemia (B-CLL), patients positive for CD38 are considered to have a poor prognosis. This project provides evidence of a functional interaction between the three ZFP36 proteins and the 3’UTR AREs of BCL2 and CD38 mRNAs. 3’UTR dual luciferase reporter assay results showed that the three ZFP36 proteins bound the 3’UTR ARE of BCL2 mRNA and CD38 mRNA. Zinc finger mutant versions of ZFP36L1 failed to bind the 3’ UTR AREs for each target, proving that intact zinc finger domains are the functional binding domains of the protein and are required for interaction with AREs. A complete ARE sequence is also needed and when mutated BCL2 3’UTR ARE was tested, lacking the adenine uridine rich core element, the BCL2 transcript was not bound by ZFP36L1 protein. For CD38 further experiments have demonstrated that down regulation of ZFP36L1 by siRNAs in HeLa cells resulted in an increase in CD38 expression as measured by immunofluorescence and flow cytometry and by Western blot analysis. These results provide further evidence that ZFP36L1 negatively regulates CD38 mRNA. Analysis of BCL2, CD38 and ZFP36L1 protein expression in primary B-CLL cells by Western blot analysis did not show an inverse relationship between the proposed targets and ZFP36L1. Protein expression analysis in B-CLL for the whole family of ZFP36 proteins showed that ZFP36L1 was heterogeneously expressed; ZFP36L2 was detected at very low levels or was undetectable and ZFP36 was low and homogeneously expressed. In cell lines representing different B cell stages, but mainly representing mature and plasma cell stages, ZFP36L2 was detected at relatively high levels but also heterogeneously and there was very low or undetectable expression of ZFP36L1 in all cells. Immunohistochemistry analysis of ZFP36L1, BCL2 and CD38 in normal lymphoid tissue and FL indicated that areas of normal lymphoid tissues associated with highest levels of BCL2 and CD38 were associated with low or undetectable levels of ZFP36L1. In FL (FL) ZFP36L1 was detected in follicular centre cells, where BCL2 is also reported to be highly expressed due to a translocation that leads to over expression of BCL2. CD38 expression was also detected within FL follicle centres with some cells showing a high level of expression within the neoplastic follicle and amongst scattered cells outside of it. Overall, the results support the hypothesis that ZFP36L1 (and also ZFP36 and ZFP36L2) negatively regulates BCL2 and CD38 mRNAs. In a wider context, the results of this project support the view that ZFP36L1, and perhaps other ZFP36 family proteins, play important roles in controlling mature B cell survival and differentiation by targeting important regulatory mRNAs in these cells. Dedication Para ti, abuela. Por ti. Contents Abstract ................................................................................................................................................................................. 2 Dedication ............................................................................................................................................................................. 3 Acknowledgments ................................................................................................................................................................ 9 Author’s declaration ........................................................................................................................................................... 10 Abbreviations ...................................................................................................................................................................... 11 Chapter 1 ............................................................................................................................................................................. 12 General Introduction........................................................................................................................................................... 12 1.1 The Zinc Finger Protein 36 (ZFP36) family .................................................................................................................. 13 1.1.2 ZFP36 proteins in post-transcriptional gene regulation ............................................................................................... 16 1.1.2.1 ZFP36 proteins RNA binding motifs .................................................................................................................... 16 1.1.2.2 Mechanism of mRNA degradation by ZFP36 proteins via adenine-uridine-rich elements .................................... 17 1.1.3 Phosphorylation of ZFP36 proteins ............................................................................................................................ 20 1.1.4 ZFP36 family proteins physiological roles ................................................................................................................... 21 1.1.5 mRNA targets for the ZFP36 protein family ................................................................................................................ 24 1.1.6 ZFP36 proteins and miRNAs ...................................................................................................................................... 25 1.1.7 Other RNA binding proteins........................................................................................................................................ 27 1.2 B lymphocytes .............................................................................................................................................................. 28 1.2.1 B cell development ..................................................................................................................................................... 29 1.2.3 B cell Malignancies .................................................................................................................................................... 31 1.2.4 B cell chronic lymphocytic leukaemia ......................................................................................................................... 33 1.3 BCL2 protein family ...................................................................................................................................................... 37 1.3.1 BCL2 and B lymphocytes: .......................................................................................................................................... 40 1.3.2 In neoplasias the expression of BCL2 is altered ......................................................................................................... 40 1.3.3 BCL2 in B-CLL ........................................................................................................................................................... 41 1.4 Cluster of differentiation 38, CD38 ............................................................................................................................... 42 1.4.1 CD38 and B lymphocytes ........................................................................................................................................... 45 1.4.2 CD38 and B-CLL ........................................................................................................................................................ 46 1.5 Aim and Objectives of the project ............................................................................................................................... 47 Chapter 2 ............................................................................................................................................................................. 49 Materials and Methods ......................................................................................................................................................
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