ZFP36 protein family members and their role in B cell functions and mRNA degradation: The human ZFP36L1 gene was isolated as an early response gene from human B lymphocytic leukaemia cells. This gene is a member of a small family consisting of three genes found in humans; ZFP36 (TIS11, TTP, Nup475, GOS24), ZFP36L1 (TIS11b, Berg36, ERF-1, BRF-1) and TIS11d (ZFP36L2, ERF-2, BRF-2). These genes encode proteins that contain two tandemly repeated zinc finger motifs through which they bind to adenine uridine (AU) rich elements (AREs) in mRNA s and mediate ARE-mediated mRNA decay. These proteins therefore have important functions in post-transcriptional regulation of gene expression. Our research is directed towards investigating the role of ZFP36L1, in particular, in normal and malignant B cells functions such as cell growth, differentiation and apoptosis.
We have evidence implicating this protein in regulation B cell apoptosis and differentiation. We are also attempting to identify important novel mRNA targets of ZFP36L1 that might be responsible for mediating effects of this protein on B cell functions.
Autoantibodies and B cells in autoimmune diseases: Work in this area has focussed on utilising molecular strategies to identify important antigenic and gene targets of lupus, transplant associated and anti-phospholipid syndrome-derived autoantibodies. We have reported that anti-phospholipid syndrome-derived anti-Beta2 GPI antibodies induce expression of a wide variety of inflammatory genes in human endothelial cells and these findings are consistent with a pathogenic role for these antibodies in anti-phospholipid syndrome. Strategies for inhibiting anti-Beta2GPI interaction with endothelial and other cells may be useful therapeutically and this is being explored.
Current research is focussed on two main research interests;
We (in collaboration with Prof. J. Norton, University of Essex) originally identified and isolated Berg36 as an early response gene from chronic lymphocytic leukaemia B cells as part of a project focusing on functional characterization of novel B-cell-derived early response genes. This work was supported by a number of UK Medical Research Council grants (MRC grant nos. G8926773, G9209876CA, G9622834). Berg36 (ZFP36L1) is a zinc finger-containing post-transcriptional regulator protein that targets mRNAs, containing AUUUA sequences in their 3'untranslated region, for degradation. It is a member of a small family of post-transcriptional proteins that also includes ZFP36 and ZFP36L2. We obtained additional funding (Leukaemia Research fund) to study the "in vivo" role of Berg36 by generating Berg36 knockout mice in collaboration with Dr. Martin Turner (The Babraham Institute, Cambridge). We have reported roles for Berg36 in apoptosis regulation of human leukaemia and lymphoma B cells. We recently reported that ZFP36L1 negatively regulates cytokine-induced plasmacytoid differentiation of BCL1 mouse leukaemia cells by targeting Blimp1 mRNA. Current research is focused on further analysis of roles for ZFP36 family proteins in normal and malignant B cells.
We were first to report the isolation and partial DNA sequence of the B-cell-derived early response gene 19A (SlamF7, CRACC, CS1) in 1990 (in collaboration with Prof. J. Norton, University of Essex) and its full open reading frame in 2000 (Genbank accession numbers AJ271869 and AJ276429). In a further publication we reported on the structure of 19A protein and provided evidence that it functioned in homotypic adhesion interactions in B cells. Current research is focused on further investigating its role(s) in normal and malignant B cells.