It is always satisfying when the hints developed by epidemiology ae shown in experiments to be true.
Some epidemiological observations ( e.g. smoking and cancer of the lung and jumping from the 22nd floor of a building is fatal) stand in their own right.
Others point the direction
One such indicator is that starvation reduces the chances of tumour development.
Lee and his colleagues in a difficult paper show a relationship between tumour development and energy starvation.
Tumour formation is a process in which the normal control mechanisms are lost. A serine/threonine kinase ( mTOR) is central to a diverse range of cellular processes important in growth and proliferation. mTOR is increased in a number of malignant processes. There are two forms of mTOR with different regulatory functions. The tumour suppressors TSC1 and TSC2 regulate mTOR.. Loss of TSC1 or TSC2 leads to a tumour called hamartoma syndrome which is a none malignant growth.
By phosphorylating TSC2, the low energy response mediator AMPK inactivates mTOR dependent growth and proliferation. This phosphorylation of TSC2 has a protective role against energy starvation mediated apoptosis ( cell death ). Other substrates phosphorylated by AMPK lead to anabolic processes being inhibited and catabolic processes being activated.
AMPK also protects the cell cycle from stress by phosphorylation of the gene p53. Protein synthesis is also prevented.
Both energy starvation and DNA damage lead to p53 activation. mTOR activity increases p53 synthesis and activation in response to both glucose starvation and DNA damage. There is phosphorylation of p53 . p53 is a potent activator of apoptosis.
By means of the AMPK-TSC-mTOR pathway , p53 forms a negative feedback loop which keeps its own synthesis in check. Cells that cannot inhibit mTOR have increased p53 activity when activated.
Lee et al (2007) Constitutive mTOR activation in TSC mutants sensitises cells to energy starvation and genomic damage via p53. The EMBO Journal vol 26, 4812-4823.
- Martin Eastwood