Research & Publications
Our lab is working to understand the molecular basis of translational control mechanisms, how signaling pathways engage them, and how defects can lead to disease. A major focus of our research is the mTOR signaling pathway, a sensor of the cellular nutrient status and a master regulator of cell growth. This pathway can elicit profound changes in the translational machinery, and is deregulated is a wide variety of diseases, including cancer, metabolic disease and neurologic disorders. We are using biochemical, bioinformatic and chemical biology approaches to understand the molecular basis of mTOR-regulated translational control mechanisms, how they are employed for normal physiologic purposes in nutrient-sensitive tissues, and how they are exploited by tumor cells to support unrestricted growth.
Specialized Terms: Growth control; RNA; Translation; Cancer biology; Signaling; Biochemistry; Bioinformatics; Metabolism
Extensive Research Description
The mammalian target of rapamycin (mTOR) pathway is an evolutionarily conserved master regulator of cell growth with important roles in metabolism, aging and cancer. The pathway senses nutrient and growth signals, and responds to these by regulating many major metabolic pathways, but particularly mRNA translation. We found that acute inhibition of mTOR selectively inhibits the translation of large class of mRNAs containing a terminal oligopyrimidine (TOP) motif at the 5’ terminus by disrupting the mRNA cap-binding complex, eIF4F. The mTOR pathway has many additional targets in the translational machinery, but the functional significance of these is unknown. We want to understand how mTOR-regulated translational mechanisms work in molecular detail, what features in mRNAs determine their dependence on mTOR activity, and how these controls are employed physiologically.
Biochemistry; Metabolism; Physiology; Translations