Salk scientists Reuben Shaw and Nathan Young
Salk Institute researchers have found that a cellular "fuel gauge" that normally controls cells' energy processes plays an important role in development. The findings may lead to a better understanding of cancer and diabetes.
Salk's Reuben Shaw previously showed that a protein complex called AMPK is crucial in preventing the heightened metabolism of tumor cells, as well as helping to return the liver function of diabetics back to normal. The findings are published in the journal Genes & Development.
AMPK has been likened to a car sensor, instructing the cell the same way a sensor would inform the driver of the gas level--triggering the driver to lower the air conditioning to conserve energy. If a cell faces a similar energy constraint, AMPK lowers cell growth and changes how energy is utilized.
"Even though there's great interest in AMPK related to diabetes and cancer, frankly nothing was known about how this fuel gauge process changes in different cell populations during development," Shaw said.
Using CRISPR, they edited out essential components of AMPK in embryonic stem cells. The importance of AMPK was only apparent when they tried to differentiate these cells. They failed to make endoderm (the innermost layer of an organism) while making too much ectoderm (the layer that becomes skin).
"These cells couldn't make the right choice," Shaw said. "This was the first inclination that this metabolic pathway is telling cells what kind of specialized tissues to become." When they studied this at a molecular level, the team found a substantial number of down-regulated genes related to an enzyme that helps degrade and recycle old cellular material--the lysosome.
The researchers pinned the absence of lysosomes to the loss of the transcription factor Tfeb, which turns on lysosomal genes when the cell becomes starved. When they reintroduced Tfeb experimentally, they could rescue the normal lysosome function and subsequent endoderm development and differentiation.
"It was thought that lysosomes and AMPK were connected somehow, but no one had dreamed that you'd get no lysosomes if you don't have this fuel gauge," says Shaw. "Connecting the AMPK pathway to lysosomes begs the question of whether this pathway is part of anti-cancer pathways as well."
Their work may help to inform scientists and clinicians on the use of lysosome inhibitors which are currently being used in a number of clinical trials for breast, lung, pancreatic and brain cancers.
- here's the release
- here's the journal abstract
Image of Reuben Shaw (left) and Nathan Young courtesy of the Salk Institute.
