Properties of the plasma membrane include
Characterization of the plasma membrane-associated prohibitins in the regulation of RAS activation and tumorigenesis
Subject area cell biology
Funding Funding since 2019
German Research Foundation (DFG) - project number 417198367
Prohibitins are evolutionarily conserved proteins that are best known for their function in the mitochondria and cristae morphogenesis. We discovered that prohibitin is required for the activation of the serine threonine kinase CRAF in the cell membrane. CRAF is the central component of the RAS-RAF-MAPK cascade, which controls fundamental processes in the cell. The RAS oncogenes are among the most important human oncogenes: Almost 30% of human carcinomas are due to mutations in RAS proteins. Since RAS is not considered pharmacologically vulnerable, the inhibitors developed so far - with modest clinical success - target downstream kinases. Since PHB1 is required for the activation of the CRAF kinase, low molecular weight inhibitors that block the interaction of PHB1-CRAF are therefore of great interest. Recently published research shows that rocaglamide inhibits this interaction and prevents activation of the CRAF-MAPK cascade in a number of cell lines. We found that PHB1 is highly expressed in NSCLC tumors and that targeted attack by cell membrane-associated PHB1 using ligands such as rocaglamide and fluorizoline prevents the activation of MEK1 in RAS mutant cell lines. In animal models, including human NSCLC xenografts and allografts, we were also able to show that treatment with rocaglamide prevents the KRAS-dependent growth of NSCLC tumors. Interestingly, rocaglamide blocks the loading of RAS with GTP in EGF-stimulated cells. Our preliminary results suggest that rocaglamide may be a RAS inhibitor and that targeted attack on PHB using chemical ligands leads to the inhibition of KRAS-mediated tumorigenesis. Therefore, we would like to investigate the following questions using a highly interdisciplinary approach that also includes chemical-biological processes: 1) How does PHB1 influence the stability of KRAS-GTP in cells? 2) Is the observed effect limited to rocaglamide, or do other flavaglines have similar properties? 3) Does rocaglamide interfere with RAS dimerization and the formation of RAS nanoclusters? 4) Do Rocaglamide also inhibit other RAS isoforms? 5) How does the PHB1 / 2 complex reach the different cell compartments? The targeted pharmacological attack on RAS has been considered the "holy grail" of cancer research for 30 years. We have identified rocaglamide, natural anti-tumor agents that work in nanomolar concentrations, as potential tools for targeting RAS in cells. The research we propose will not only provide important insights into how PHB and RAS work, but will also open up a new therapeutic option for the treatment of RAS-dependent human tumors.
DFG procedureSach grants
- Is it possible to regenerate nerve damage
- Which singer sings many songs
- Fits an S7 + cover to an S7
- What is the speed of antineutrino
- What is the best language translator app
- How do you overclock Nvidia GPUs
- What is wave speed
- What is the use of high bandwidth
- What are some great business docs
- How do you remove fireplace doors
- Does an anesthetist perform an operation
- What is Windows Installer in Task Manager
- How to pronounce mon dieu
- Some good progressive rock metal bands
- Can I refuse entry to the landlord?
- Haxe is a good programming language
- How logical is the Portuguese spelling
- What recordings do kitties need and when
- Why are most marine aquariums indoors
- What company started mobile money
- Can HDMI cables be of poor quality?
- Which vehicle features have disappeared over time?
- What are the different zed combos
- Who is your favorite espionage novelist?
- Is Krylon spray paint based on oil
- Is it difficult to crack the GATE exam?
- What are surgical interventions
- How do you wear a beret correctly
- How to program a Honeywell thermostat
- Why doesn't Chipotle have any seafood
- What are non-valent metals
- Urinating aquatic animals
- Should I practice self-discipline or luck?
- Why do nails crack?