Dr. Sonenberg studies the molecular basis of the control of protein synthesis in eukaryotic cells and its importance in diseases such as cancer, obesity, diabetes and neurological diseases. His research program is as follows:
1) Translational control of cancer:
Dr. Sonenberg and his team discovered the eIF4E-binding proteins (4E-BPs). 4E-BPs are phosphoproteins, and their phosphorylation status modulates their interaction with eIF4E. The PI3K/Akt/mTOR signaling pathway, whose components are mutated in many cancers, mediates 4E-BP phosphorylation and thus regulates translation. He studies their function and control of the mTOR signaling pathway. Furthermore, the Sonenberg lab discovered that eIF4E is phosphorylated downstream of the RAS/MAPK pathway, thus positioning translation initiation at the convergence of both mTOR and RAS signaling. In a recent discovery they showed that prevention of eIF4E phosphorylation reduces tumor growth, and importantly, prevents the development of metastases. They are now collaborating with the pharmaceutical industry to discover drugs that inhibit eIF4E phosphorylation. Most recently, Dr Sonenberg's team has initiated studies in a previously unsuspected role for translational control in the tumor microenvironment. They are currently dissecting the ways in which the numerous non-transformed cells, which are crucial for tumor biology, regulate eIF4E to affect cancer progression.
Click here to see the illustration of the translational control of the tumor microenvironment!
2) Viruses as anti-cancer drugs:
For instance, the mammalian kinase target of rapamycin (mTOR) stimulates interferon production via phosphorylation of its effector proteins, 4E-BPs and S6Ks. Sonenberg’s group used this knowledge to employ a pharmacoviral approach to treat malignant gliomas (MGs). The highly specific inhibitor of mTOR rapamycin, in combination with vesicular stomatitis virus (VSV), dramatically increased the survival of immunocompetent rats bearing MGs. More importantly, VSV selectively killed tumor, but not normal cells, in MG-bearing rats treated with rapamycin. In fact, mTOR inhibition appears to decrease viral infection in normal cells, while increasing viral infection in transformed cells. We are now delineating the mechanism by which this occurs. These results show that targeting tumors through inhibition of mTOR in combination with oncolytic viruses is an effective strategy to augment therapeutic activity in cancer. Our current focus is to delineate through high-throughput strategies the impact of translation control and how it can be best suited for specific oncolytic viral therapeutic contexts.
3) Mechanism of miRNA action in translation and mRNA decay:
MicroRNAs are small non-coding RNAs (~21 nucleotides) that play an important role in gene regulatory networks in animals and plants. miRNAs play major roles in cancer development, progression and metastasis. It is estimated that ~70% of mammalian genes are regulated by miRNAs, but their mechanism of action is not well understood. Sonenberg et al developed an in vitro system from mouse cells that recapitulates the function of miRNAs in cells and showed that miRNAs first inhibit initiation of mRNA translation and subsequently cause deadenylation of mRNAs. These findings will help in understanding the role that miRNAs play in cancer development.
4) Control of Neural Translation in
Neurons carry out sophisticated computations as part of a network that orchestrates complex behaviours. Translational control of the pre- and post-synaptic proteome is essential for the balance of excitatory and inhibitory (E/I) synaptic transmission. E/I imbalances have been reported in Autism Spectrum Disorders, Schizophrenia and Depression. We are elucidating the translational mechanisms governing neural protein synthesis in the CNS. For this purpose, we use several transgenic and inducible mouse models, targeting pathways up- and downstream of the translation initiation factors, eIF2α and eIF4E. Furthermore, we combine analysis of specific behaviours, changes in synaptic plasticity and dendritic morphology. Targeting changes on these pathways should facilitate the design of novel therapeutic avenues.
4.a) IDRC funded research project and progress update. Click here for more details!