Rubrik: Science Life
Published: 10.05.2007 06:00
Modified: 09.05.2007 21:33
Two ETH Zurich biologists have discovered important signal pathways that allow kidney cells to degenerate. This is the fault of inactive proteins that cannot maintain the cells’ antennae, the cilia.
Radios need them and so do insects, and a seal would starve if it could not count on them. What they need are antennae, feelers or muzzle hairs, all of them systems that pick up signals from the environment and pass them on to somewhere – transistors or circuits in a radio or in the brain - where they are processed.
However cells, and with them entire organs in the human body, also rely on antennae. For example what are known as primary cilia sit on the surface of epithelial cells in the kidney tubules. Their function is to record urine flow and chemical signals. If these antennae disappear, this has fatal consequences for the whole body. The epithelial cells degenerate and begin uncontrolled proliferation. They form cysts – at best a precursor of dangerous kidney cancer. Up to now the cause of the cilia’s disappearance was unknown.Inactive proteins responsible for degradation
However, two ETH Zurich researchers, doctoral student Claudio Thoma and post-doc Ian Frew in Professor Wilhelm Krek’s group at the Institute for Cell Biology, have now elucidated a mechanism that leads to the loss of primary cilia. In particular they identified two proteins responsible for maintaining the mini-antennae. If only one of the two is missing, the other can make up for the loss, the antennae are preserved and the cells are under control. However, if both are absent the cells are degraded and cysts form. This is reported in the issue of “Nature Cell Biology” on Wednesday 2 May 2007.(1)
The first protein, called pVHL, is attached to the microtubules forming the framework inside the cilium. The second protein, the kinase GSK3beta, is equally responsible for the construction and stability of the microtubules and can therefore ensure the maintenance and structure of the cilium even on its own. However, it is detrimental to the cilia if both molecules are inactive at the same time. This happens to people suffering from hereditary Von Hippel-Lindau disease. They develop pathological kidney cysts, mostly benign, were cilia can scarcely be found any longer. This is caused by a mutation on the VHL gene, which produces an inactive form of pVHL. However, in the cysts GSK3beta is also fatally inactive. That promotes the degradation of the important cell antennae.
How GSK3beta is inactivated in cysts is unclear. Mutations on other genes so far not identified could be responsible. Doctoral student Thoma says “However, the essential point is that the two signal pathways coupled to one another are needed to maintain the cilia, otherwise they are destroyed.”The same result in mice and cell lines
Initially the two scientists worked independently of each other on other projects, and the discoveries are “just a by-product” of their work. In his thesis, Thoma originally wanted to find out how pVHL and microtubules interact. Frew on the other hand was working on mouse models to gain a better understanding of the origin of kidney cancer. Both stumbled across the same phenomenon during their research and obtained the same result with different methods. Thoma worked with cell lines, Frew with mouse kidneys. Frew stresses that “Finding the two signal pathways in both systems was a lucky coincidence.” On the other hand the present result arose mainly thanks to their exceptionally good collaboration .
Kidney cancer is responsible for 2.5 percent of all cancer disease in adults. The commonest is clear cell kidney carcinoma, and the gene for pVHL is mutated in 80 percent of these patients. However, researchers still do not know how the cysts turn into a malignant cancer. Frew und Thoma suspect other underlying signal pathways and are researching them. A better understanding of these signal pathways could provide possible starting points for therapies for kidney cancer patients.Footnotes: