Post-transcriptional regulation

Research Team:  Carthew, Sontheimer, Uhlenbeck, Volpe, Wu, Morimoto, Matouschek, Weiss, Lomasney

RNA splicing and silencing, translation (Carthew, Sontheimer, Uhlenbeck, Volpe, Wu)
The CCB program has significant strength is cellular regulation at the level of RNA processing. Carthew and Sontheimer elucidated several steps in the biochemical mechanism by which micro RNAs regulate gene expression through their characterization of functional complexes on the RNAi pathway. This pathway is currently attracting a large amount of interest because it is becoming increasingly clear that it is involved in the regulation of many cellular processes. In addition to the fundamental mechanistic studies Carthew, investigates how small RNAs regulate RTK signaling and cell cycle transitions and Volpe how they regulate chromatin structure. Uhlenbeck is a distinguish senior biochemist analyzing the fundamental properties of RNA biochemistry with a major focus on the molecular recognition events during translation. Carthew and Sontheimer are also developing RNAi technology for applications in research and therapy.

Protein folding, degradation, and modification (Morimoto, Matouschek, Weiss, Lomasney)
After translation, most proteins fold into well-defined three-dimensional structures and then function for different times inside and outside the cell. Chaperones assist many proteins in folding transition and gross conformational changes after synthesis and some biochemical processes. Damaged or misfolded proteins are removed from the cell by ATP-dependent proteases. Morimoto and Matouschek investigate the biochemistry and molecular biology of these two classes of catalysts involved in maintaining cellular protein homeostasis. Neoplastic transformation leads to an upregulation of the chaperone response and inhibition of this response sensitizes cancerous cells. Morimoto is also developing drugs that interfere with the chaperone response and, in collaboration investigates how these drugs affect transformed cells. ATP-dependent proteases play a central role in cellular regulation by controlling the concentrations of hundreds of regulatory proteins. The most important of these proteases in eukaryotic cells is the proteasome. Proteins are targeted to the proteasome through post-translational modification with ubiquitin. Matouschek investigates how the proteasome recognizes, unfolds and degrades its substrates. The work on these protein machines has provided insights into cellular regulation, for example by discovering a novel signal for protein processing by the proteasome. Another widespread posttranslational modification is protein phosphorylation by kinases. Weiss investigates how kinase signaling pathways regulate cell morphology by coordinating cytoskeleton organization, membrane trafficking and gene expression. Changes in cell shape are an important hallmark of cancer progression. Weiss's work provides the basis for investigations of these changes and may identify novel therapeutic targets. Lomasney studies the mechanisms of phosphoinositide-mediated signaling and its perturbation in human cancer. Phosphoinositide metabolism is a critical signaling step upstream of a number of cancer-associated protein kinase pathways, including protein kinase-C, and one of important therapeutic targets against cancer.

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