Dr Jonathan L Dean
Department of Medicine
Tel: +44 (0)20 3313 4470
Dr Jonathan L Dean
The aim of research in my group is to unravel the molecular mechanisms that underpin inflammatory gene expression. Our research is centred around the p38 mitogen-activated kinase pathway which stabilises otherwise unstable AU-rich-element-containing mRNAs of the inflammatory response (1). p38 stabilises inflammatory mRNAs by blocking the obligatory first step in mRNA decay namely deadenylation or removal of the poly-(A) tail (2). The RNA-binding protein tristetraprolin (TTP) binds AU-rich elements in inflammatory mRNAs and is regulated by phosphorylation by MK2, a kinase downstream of p38. Phosphorylation of TTP by MK2 inhibits the mRNA-destabilising function of TTP, thereby stabilising inflammatory mRNAs and increasing their expression (3). We have recently identified CCR4-CAF1 as the major deadenylase complex that is utilised by TTP and shown that MK2 stabilises mRNA by inhibiting CCR4-CAF1 recruitment (4). Current research in my group continues to focus on post-transcriptional regulation of inflammatory gene expression.
A new direction of our research is the investigation of another MK2 substrate, the small heat shock protein, hsp27. In an RNAi screen for MK2 substrates that regulate inflammatory gene expression we discovered that hsp27 is needed for the expression of pro-inflammatory mediators such as cyclooxygenase-2, IL-6 and IL-8 (5). We further showed that hsp27 enhances signalling downstream of TAK1, a pivotal kinase that activates the p38, JNK and NF-kB pathways (5). Future work will investigate the function of HSP27 in the inflammatory response and the mechanisms involved.
1: Dean JL, Brook M, Clark AR, Saklatvala J. p38 mitogen-activated protein kinase regulates cyclooxygenase-2 mRNA stability and transcription in lipopolysaccharide-treated human monocytes. J Biol Chem. (1999) 274(1):264-9.
2: Dean JL, Sarsfield SJ, Tsounakou E, Saklatvala J. p38 Mitogen-activated protein kinase stabilizes mRNAs that contain cyclooxygenase-2 and tumor necrosis factor AU-rich elements by inhibiting deadenylation. J Biol Chem. (2003) 278(41):39470-6.
3: Tudor C, Marchese FP, Hitti E, Aubareda A, Rawlinson L, Gaestel M, Blackshear PJ, Clark AR, Saklatvala J, Dean JL. The p38 MAPK pathway inhibits tristetraprolin-directed decay of interleukin-10 and pro-inflammatory mediator mRNAs in murine macrophages. FEBS Lett. (2009) 583(12):1933-8.
4: Marchese FP, Aubareda A, Tudor C, Saklatvala J, Clark AR, Dean JL. MAPKAP kinase 2 blocks tristetraprolin-directed mRNA decay by inhibiting CAF1 deadenylase recruitment. J Biol Chem. (2010) 285(36):27590-600.
5: Alford KA, Glennie S, Turrell BR, Rawlinson L, Saklatvala J, Dean JL. Heat shock protein 27 functions in inflammatory gene expression and transforming growth factor-beta-activated kinase-1 (TAK1)-mediated signaling. J Biol Chem. (2007) 282(9):6232-41.