The pathogenesis of mesothelioma is driven by a dysregulated translatome.

Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. The disease primarily results from loss of tumour suppressor gene function and there are no 'druggable' driver oncogenes associated with MpM. To identify opportunities for management of this disease we have carried out polysome profiling to define the MpM translatome.

MicroRNA in situ hybridization in tissue microarrays.

In situ hybridization is used to visualize nucleic acids in microscopic tissue sections and has in recent years been used successfully to detect microRNAs. We have further optimized a technique to detect and semiquantitatively assay microRNA expression in tissue microarrays derived from formalin-fixed paraffin-embedded archival tumor tissue.

Dysregulation of protein synthesis and disease.

The regulation of protein synthesis plays as important a role as transcriptional control in the control of gene expression. Once thought solely to act globally, translational control has now been shown to be able to control the expression of most genes specifically. Dysregulation of this process is associated with a range of pathological conditions, notably cancer and several neurological disorders, and can occur in many ways.

Identification of a motif that mediates polypyrimidine tract-binding protein-dependent internal ribosome entry.

We have identified a novel motif which consists of the sequence (CCU)(n) as part of a polypyrimidine-rich tract and permits internal ribosome entry. A number of constructs containing variations of this motif were generated and these were found to function as artificial internal ribosome entry segments (AIRESs) in vivo and in vitro in the presence of polypyrimidine tract-binding protein (PTB). The data show that for these sequences to function as IRESs the RNA must be present as a double-stranded stem and, in agreement with this, rather surprisingly, we show that PTB binds strongly to double-stranded RNA.