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Topic Name: Discovered important signal pathways that allow kidney cells to degenerate
Category: Biodesign
Research persons: Claudio Thoma,About Researchers:
Location: Institute of Cell Biology,ETH Hönggerberg, Building HPM,Schafmattstrasse 18,CH-8093 Zürich, Switzerland
Details
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 degradationHowever, 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.
About Researchers:
Prof. Wilhelm Krek
Institute of Cell Biology
Schafmattstrasse 18
ETH-Hönggerberg, p;Kuerzel=HPM,&-find">HPM,
F 42
CH-8093 Zürich
Phone: +41 44 633 34 47
Fax: +41 44 633 13 57
E-Mail:wilhelm.krek@cell.biol.ethz.ch
Claudio Thoma
Institut f. Zellbiologie
Schafmattstr. 18
ETH-Hönggerberg, HPM
F 46
CH-8093 Zürich
Phone: +41 44 633 33 54
E-Mail:
claudio.thoma@cell.biol.ethz.ch
Funded:
Intellectual
life at ICB is being further enriched through the participation of Institute
members in new interdisciplinary centers at ETH Zurich, such as the Neuroscience
Center Zurich, the NCCR
Neuro, the BEST Cluster
for Bioengineering, the Competence
Center for Systems Physiology and Metabolic Disease and SystemsX.
In The Images:
1.Prof. Wilhelm Krek
2.The
cilia, fluorescing green, can easily be seen in a kidney tubule. (Photo:
Frew/Thoma, Inst. for Cell Biology, ETH Zurich)
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