Regulation of cell proliferation

Cell homeostasis during development is maintained through a finely regulated balance between proliferation and cell death. Understanding the regulatory mechanisms that drive these processes in response to stress and other environmental triggers is of vital importance for health and disease.

Scientists on the EU-funded MIRNASTRESS project aimed to investigate the regulation of key apoptosis and cellular proliferation genes (p21, c-myb, c-myc). These genes are central to cell cycle regulation and progression and mutations are encountered in various forms of cancer. MIRNASTRESS focused on the regulation of the messenger RNA (mRNA) in these genes with respect to synthesis, translation and decay.

Special attention was given to the nucleic acid binding proteins: RBM38 and FIR. Specifically, researchers worked to understand the mechanism by which these proteins recognise and regulate the translation of the target mRNA molecules. Dysfunction of these two regulatory mechanisms is closely associated with specific cancers and is therefore of high therapeutic significance.

Researchers discovered that in cells exposed to stress, RBM38 competes with microRNAs to stabilise specific mRNAs required by p53 to regulate cell proliferation and apoptosis. Structural analysis of RBM38 unveiled the microRNA binding sites and provided vital insight into the mechanism by which RBM38 destabilises the microRNA-mRNA complex.

Upstream of the p21 and c-myc genes, scientists identified a regulatory region implicated in gene transcription. They went on to investigate the structural interaction between FIR and this region hoping to validate the potential of FIR to modulate gene expression and act as an anticancer target.

Taken together, the observations of the MIRNASTRESS study unveil the existence of a regulatory mechanism that controls post-translational gene expression through inhibition of microRNA activity. These findings disclose a novel way of p21 and c-myc regulation and provide the molecular basis to design anti-cancer strategies in the future.