Position: James McGill Professor
Affiliation:

Rosalind and Morris Goodman Cancer Research Centre

Department of Biochemistry

Contact:

Rosalind and Morris Goodman Cancer Research Centre
1160 Pine Ave W., Office: Room 615; Lab: Room 608
Montréal, QC H3A 1A3

Tel:  Office: (514) 398-7274; Lab: (514)398-7275
Fax: (514) 398-1287

nahum.sonenberg@mcgill.ca

Nahum Sonenberg homepage

Research

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 cancer related research program is as follows:

1)    Translational control of cancer: Regulation of translation in eukaryotes occurs primarily at the initiation step, mediated by eukaryotic Initiation Factors (eIFs). A key player is the mRNA 5’ cap-binding protein eIF4E, which is the limiting translation initiation factor in most cells, and whose forced excessive expression in mice causes cancer. eIF4E is elevated in several human cancers. Consistent with its critical role in cell growth, the amount of active eIF4E is regulated at several levels:

a) transcription
b) phosphorylation
c) binding to repressor proteins, the eIF4E-binding proteins (4E-BPs).

Dr. Sonenberg and his team discovered the function and control of the 4E-BPs by the signaling pathways involved in 4E-BP and eIF4E phosphorylation. They discovered that Ras signaling activates Mnk, which directly phosphorylates eIF4E on Ser209. In a recent discovery they showed that prevention of eIF4E phosphorylation reduces tumor growth. They are now collaborating with the pharmaceutical industry to discover drugs that inhibit eIF4E phosphorylation. 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.

2)    Viruses as anti-cancer drugs: building a safer and more selective oncolytic virus to treat cancer: Oncolytic viruses replicate better in cancer cells than in normal cells, destroying the tumors in which they replicate. A key discovery explaining the preferential replication of viruses in tumors was that cancer cells cannot respond well to the protein interferon, which is secreted by immune cells, and is the first defense mechanism of the organism against viral infections. One of the best-characterized oncolytic viruses is vesicular stomatitis virus (VSV), which does not normally infect humans. VSV propagates efficiently in tumors, unlike in normal cells. The differential VSV susceptibility of normal versus transformed cells is due to mutations in the interferon pathway.


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 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. These results show that reducing tumor growth through inhibition of mTOR is an effective strategy to augment therapeutic activity in cancer.

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 in vitro systems from mouse cells that recapitulate the function of miRNAs in cells and showed that miRNAs inhibit initiation of mRNA translation and cause deadenylation of mRNAs. These new findings will help in understanding the role that miRNAs play in cancer development.

Dr. Sonenberg’s recent publications