Post-Transcriptional Regulation of BCL2 mRNA by the RNA-Binding Protein ZFP36L1 in Malignant B Cells

Zekavati, A., Nasir, A., Alcaraz, A., Aldrovandi, M., Marsh, P., Norton, J.D. and Murphy, J.J. 2014. Post-Transcriptional Regulation of BCL2 mRNA by the RNA-Binding Protein ZFP36L1 in Malignant B Cells. PLoS ONE. doi:10.1371/journal.pone.0102625

TitlePost-Transcriptional Regulation of BCL2 mRNA by the RNA-Binding Protein ZFP36L1 in Malignant B Cells
AuthorsZekavati, A., Nasir, A., Alcaraz, A., Aldrovandi, M., Marsh, P., Norton, J.D. and Murphy, J.J.
Abstract

The human ZFP36 zinc finger protein family consists of ZFP36, ZFP36L1, and ZFP36L2. These proteins regulate various cellular processes, including cell apoptosis, by binding to adenine uridine rich elements in the 3′ untranslated regions of sets of target mRNAs to promote their degradation. The pro-apoptotic and other functions of ZFP36 family members have been implicated in the pathogenesis of lymphoid malignancies. To identify candidate mRNAs that are targeted in the pro-apoptotic response by ZFP36L1, we reverse-engineered a gene regulatory network for all three ZFP36 family members using the ‘maximum information coefficient’ (MIC) for target gene inference on a large microarray gene expression dataset representing cells of diverse histological origin. Of the three inferred ZFP36L1 mRNA targets that were identified, we focussed on experimental validation of mRNA for the pro-survival protein, BCL2, as a target for ZFP36L1. RNA electrophoretic mobility shift assay experiments revealed that ZFP36L1 interacted with the BCL2 adenine uridine rich element. In murine BCL1 leukemia cells stably transduced with a ZFP36L1 ShRNA lentiviral construct, BCL2 mRNA degradation was significantly delayed compared to control lentiviral expressing cells and ZFP36L1 knockdown in different cell types (BCL1, ACHN, Ramos), resulted in increased levels of BCL2 mRNA levels compared to control cells. 3′ untranslated region luciferase reporter assays in HEK293T cells showed that wild type but not zinc finger mutant ZFP36L1 protein was able to downregulate a BCL2 construct containing the BCL2 adenine uridine rich element and removal of the adenine uridine rich core from the BCL2 3′ untranslated region in the reporter construct significantly reduced the ability of ZFP36L1 to mediate this effect. Taken together, our data are consistent with ZFP36L1 interacting with and mediating degradation of BCL2 mRNA as an important target through which ZFP36L1 mediates its pro-apoptotic effects in malignant B-cells.

JournalPLoS ONE
Year2014
PublisherPublic Library of Science
Publisher's versionAlcaraz_Murphy_etal_2014.pdf
Digital Object Identifier (DOI)doi:10.1371/journal.pone.0102625
Web address (URL)http://dx.doi/org/10.1371/journal.pone.0102625
Publication dates
Published11 Jul 2014
LicenseCC BY 3.0

Related outputs

STAT5 in Cancer and Immunity
Murphy, J.J. and Rani, A. 2016. STAT5 in Cancer and Immunity. Journal of Interferon & Cytokine Research. 36 (4), pp. 226-237. doi:10.1089/jir.2015.0054

ZFP36 proteins and mRNA targets in B cell malignancies
Alcaraz, A. 2015. ZFP36 proteins and mRNA targets in B cell malignancies. PhD thesis University of Westminster Biomedical Sciences

Evidence for targeting of CD38 mRNA by the post-transcriptional regulator protein ZFP36L1
Murphy, J.J. 2015. Evidence for targeting of CD38 mRNA by the post-transcriptional regulator protein ZFP36L1. 4th European Congress of Immunology. Vienna 08 Sep 2015

The Notch target Hes1, is a STAT5 target gene with implications in cancer
Rani, A., Greenlaw, R., Galustian, C. and Murphy, J.J. 2015. The Notch target Hes1, is a STAT5 target gene with implications in cancer. 2015 Meeting of the ICIS in Bamberg, Germany, October 11th -14th. Bamberg, Germany Oct 2015 doi:10.1016/j.cyto.2015.08.214

ZFP36L1 negatively regulates plasmacytoid differentiation of BCL1 cells by targeting BLIMP1 mRNA
Nasir, A., Norton, J.D., Baou, M., Zekavati, A., Bijlmakers, M.J., Thompson, S. and Murphy, J.J. 2012. ZFP36L1 negatively regulates plasmacytoid differentiation of BCL1 cells by targeting BLIMP1 mRNA. PLoS ONE. 7 (12), p. e52187. doi:10.1371/journal.pone.0052187

AU-rich RNA binding proteins in hematopoiesis and leukemogenesis
Baou, M., Norton, J.D. and Murphy, J.J. 2011. AU-rich RNA binding proteins in hematopoiesis and leukemogenesis. Blood. 118 (22), pp. 5732-5740. doi:10.1182/blood-2011-07-347237

Involvement of Tis11b, an AU-rich binding protein, in induction of apoptosis by rituximab in B cell chronic lymphocytic leukemia cells
Baou, M., Jewell, A.P., Muthurania, A., Wickremasinghe, R.G., Yong, K.L., Carr, R., Marsh, P. and Murphy, J.J. 2009. Involvement of Tis11b, an AU-rich binding protein, in induction of apoptosis by rituximab in B cell chronic lymphocytic leukemia cells. Leukemia. 23 (5), pp. 986-989. doi:10.1038/leu.2008.340

Post-transcriptional regulator protein ZFP36L1 targeting of Bcl-2 mRNA
Zekavati, A., Marsh, P. and Murphy, J.J. 2009. Post-transcriptional regulator protein ZFP36L1 targeting of Bcl-2 mRNA. 2nd European Congress of Immunology. Berlin, Germany 13 – 16 September 2009

Evidence for involvement of ZFP36L1 protein downregulation in differentiation of the murine BCL1 leukaemia cell line
Nasir, A., Roberts, H., Thompson, S. and Murphy, J.J. 2009. Evidence for involvement of ZFP36L1 protein downregulation in differentiation of the murine BCL1 leukaemia cell line. 2nd European Congress of Immunology. Berlin, Germany 13 – 16 September 2009

TIS11 family proteins and their roles in post-transcriptional gene regulation
Baou, M., Jewell, A.P. and Murphy, J.J. 2009. TIS11 family proteins and their roles in post-transcriptional gene regulation. Journal of Biomedicine and Biotechnology. doi:10.1155/2009/634520

Evidence for involvement of ZFP36L1 protein downregulation in differentiation of the murine BCL1 leukaemia cell line
Nasir, A., Roberts, H., Thompson, S. and Murphy, J.J. 2008. Evidence for involvement of ZFP36L1 protein downregulation in differentiation of the murine BCL1 leukaemia cell line. BSI Immunology Congress. Glasgow 17-21 November 2008

Mode of action of Rituximab in chronic lymphocytic leukaemia: activation of Tis11b, an inducer of mRNA instability and induction of apoptosis
Baou, M., Jewell, A.P., Yong, K.L. and Murphy, J.J. 2008. Mode of action of Rituximab in chronic lymphocytic leukaemia: activation of Tis11b, an inducer of mRNA instability and induction of apoptosis. in: Moreau, I.B. (ed.) Chronic lymphocytic leukemia: new research Nova Science Publishers. pp. 141-155

Permalink - https://westminsterresearch.westminster.ac.uk/item/9538x/post-transcriptional-regulation-of-bcl2-mrna-by-the-rna-binding-protein-zfp36l1-in-malignant-b-cells


Share this
Tweet
Email