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School of Medicine
April 18–22, 2009
New Orleans, La.
CHIPPING AWAY AT PROTEINS
A protein chip approach to unraveling networks and pathways
Protein Synthesis and Turnover Meeting: Target Identification and Pathway Mining Room 352; Tuesday, April 21, 3:30 to 5:50 p.m.
The more scientists learn about how proteins work, the closer we are to understanding what goes wrong in diseases such as cancer. Researchers at Johns Hopkins will prese nt the latest development in protein chip technology and its applications in profiling DNA-protein interactions in humans and how protein acetylation regulates lifespan in yeast.
The team is surveying all protein-DNA interactions (PDIs) in human cells, with the aim of learning more about the human protein-DNA “interactome” to better understand aberrant interactions that lead to disease states.
Using protein chips, the research team also is documenting how posttranslational modifications of lysine by the NuA4 complex can affect the function of certain yeast proteins. Specifically, the team found that the acetylation status of the core enzyme, Esa1, is important for regulating the gluconeogenesis pathway and therefore contributes to aging in the budding yeast.
“We started studying proteins because their activity was not completely understood,” says Zhu, an assistant professor of pharmacology and molecular sciences and member of the High Throughput Biology Center at Johns Hopkins. “We were very surprised to find that some of these proteins, including Esa1, act on substrates in an area of the cell where we were not expecting to see such activity.”
THE PROMISE OF CHEMICAL RESCUE
Tyrosine Kinase Mechanisms and Pathways
Protein Synthesis and Turnover Meeting: Tyrosine Kinases in Cancer Room 357; Monday, April 20, 9:55 to 12:15 pm.
Enzymes known as protein tyrosine kinases (PTKs) are associated with many types of cancers, including chronic myeloid leukemia and non-small cell carcinoma. Likewise, they are the focus of efforts to design new drug treatments such as Gleevec (Imantinib mesylate), which targets a type of leukemia.
Researchers at Johns Hopkins are currently studying PTKs using a technique that is unique to their laboratory called chemical rescue. Chemical rescue allows researchers to inactivate and reactivate enzymes to better study how they work. “The chemical rescue approach is similar to trying to understand how a car moves,” says Philip Cole, M.D., Ph.D., the E.K. Marshall and Thomas H. Maren Professor and director of pharmacology and molecular sciences. “You can watch a car drive along the highway or you can observe someone as they turn the ignition. Both approaches describe movement, but are different because they focus on different aspects of how the car moves.”
Cole and colleagues have focused their work on three PTKs: Src, which is associated with inflammatory diseases and cancer; Abl, the target of the leukemia drug, Gleevec; and EGFR, the target of the drug Tarceva (erlotinib), a treatment for lung cancer. By better understanding these PTKs, scientists can potentially open the door to even more treatments for cancer and other diseases. “We are always considering the therapeutic angle when we are considering these studies.” says Cole.
HOW CELLS FOLLOW THEIR "NOSE"
Signaling Networks in Chemotaxis and Cystokinesis
Protein Synthesis and Turnover Meeting: Phosphatidylinositol Signaling and Metabolism Room 357; Tuesday, April 21, 9:55 to 12:15 pm.
Cell movement is essential for life and critical for immune system function and embryonic development. Cell biologists at Johns Hopkins are combining genetic analysis with live imaging technology to learn how cells move toward chemical signals, called chemoattractants, in their environment.
By manipulating proteins on the surface of Dictyostelium amoebae, the researchers have determined that a signaling pathway involving the lipid PIP3 is important for sensing and responding to gradients of chemoattractants. PIP3 is specifically generated on the front edge of the cell that faces the higher local concentration of chemoattractant and leads to cytoskeletal changes that accompany cell movement. The team also has discovered that Dictyostelium shares some similarities — molecularly, anyway — with human cell movement.
“It is pretty remarkable that much of what we have learned using these amoeboe cells is conserved in human cells,” says Peter Devreotes, Ph.D., professor and director of cell biology at Hopkins. “The same pathways in both contribute to directing cell movement.”