MIRNASTRESS

miRNASTRESS: structural and functional study of the RBM38-controlled mechanism of mRNA stabilization

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 Obiettivo del progetto (Objective)

'The aim of the research activities detailed in this proposal is to understand how the RNA-binding protein RBM38 mediates the cellular stress response —the series of cellular events triggered by diverse harmful factors to restore cellular homeostasis— by modulating the activity of microRNAs on specific targets. Our objective is to determine the molecular mechanism by which RBM38 interferes with the binding of miRNAs on a selection of messenger RNAs that are targets of the tumor suppressor p53, a protein which guards the genomic integrity and regulates the stress response. The normal cellular stress response is crucial to restore or reprogram various gene-expression patterns that maintain homeostasis. Failure in this response can lead to severe pathological conditions, such as cancer. Understanding the mechanisms that mediate the stress response at the molecular level is thus one of the most important open questions in cell biology today and has a clear impact in molecular medicine and in the pharmaceutical industry. We will use state-of-the-art biophysical techniques to identify the molecular and biophysical basis of RNA recognition by RBM38. We will propose a mechanism to explain how RBM38 controls post-translational gene expression through the inhibition of miRNA activity. Our research will provide the molecular rationale for a key mechanism of cell regulation and will advance our knowledge of the biology involved in the development of cancer. miRNASTRESS will address a gene-regulation mechanism based on the interference of miRNA activity and will provide the necessary structural information to tune the activity of RBM38. Building on our study and on the know-how accumulated on RNA recognition motif-RNA interactions, we aim to use the RBM38 high-resolution structure as a protein template to develop small molecular weight compounds with therapeutic valence that interfere with the RBM38 biological function.'

Introduzione (Teaser)

Cancer is characterised by uncontrolled cell proliferation. To identify new targets for therapy, European researchers concentrated on the mechanisms underlying cell proliferation.

Descrizione progetto (Article)

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.