公開ラボセミナー
Translational control of cancer development and metastasis
Nahum Sonenberg（McGill University）
2015年11月02日(月) 17：00-18：00 理学部3号館327号室
mRNA translation is a key target for the control of protein homeostasis in the cell. Control of translation initiation plays an important role in cell growth, proliferation and in diseases, such as cancer. mRNA translation is dysregulated in many cancers via a combination of protein overexpression and defects in the pathways that signal to the translation machinery. In support of the critical function of translational control in cancer is the discovery of mutations in translational components in genetic syndromes associated with cancer susceptibility. The hyperactivation of the mechanistic/mammalian target of rapamycin (mTOR), which controls translation rates, occurs in the majority of cancers.
A key component of translation initiation is the mRNA 5’-cap-binding protein, eIF4E. eIF4E overexpression transforms rodent and human cells and causes cancer in mice. eIF4E levels are elevated in several types of cancers. Phosphorylation of eIF4E on Ser209 is required for efficient transformation by eIF4E. In addition, Ser209 is required for cancer metastasis.
Important downstream targets of the PTEN/Akt/mTOR signaling pathway, which are strongly implicated in cancer etiology, are the 4E-BPs (eIF4E-binding proteins), which bind to eIF4E and inhibit cap-dependent translation. mTOR forms two distinct complexes, mTORC1 and mTORC2. mTORC1 integrates growth factor and nutrient signals to control cell proliferation (increase in cell number) and cell growth (increase in mass). mTORC1 controls these processes by stimulating mRNA translation via phosphorylation of its two major downstream targets: the 4E-BPs (4E-BP1, 2 and 3) and the S6 kinases (S6K1 and 2).
