Protein triggers a snowball effect
If a certain protein is missing in kidney cells, fatal cell division errors arise, which can finally lead to genetically unstable cells and to renal cancer. ETH researchers tracked down the phenomenon.
Body cells divide incessantly. This is actually a "standard procedure", which in most cases proceeds without error. Particularly important during cell division, known as mitosis, is the correct distribution of the chromosomes to the new daughter cells. This requires that a spindle of microtubules is formed in the cell during the division, with the aid of which the chromosomes are pulled to the opposite poles.
Here, the fidelity-monitoring checkpoint system plays an important role. It supervises whether all chromosomes are correctly bound to the spindle microtubules. This checkpoint is activated, if errors arise during cell division, which would lead to an unequal distribution of the chromosomes on the daughter cells. The spindle checkpoint can halt cell division for as long as necessary, until the chromosomes are correctly attached to the spindle microtubulues.
Fatal consequences upon loss of a protein
With this mechanism the cell prevents the formation and accumulation of cells with abnormal sets of chromosomes. Now, however, in a publication in "Nature Cell Biology" two ETH researchers, the cell biologist Claudio Thoma from the Wilhelm Krek working group and the biochemist Alberto Toso from the Patrick Meraldi group, have identified a mechanism, which triggers an unwanted and fatal snowball effect, which can lead to kidney cells with deviating chromosome numbers and contribute to kidney cancer development.
Central to this mechanism is the von Hippel Lindau tumor suppressor protein (pVHL). During cell division this molecule is deposited on the spindle apparatus. If pVHL is missing, the cells divide incorrectly. The spindle cannot align itself correctly and changes its position like a defective compass needle. The spindle checkpoint is also weakened. With a loss of pVHL cell division continues, chromosomes are lost; cells with incomplete or overstaffed chromosome sets develop. Aneuploid cells emerge, which contain the wrong number of chromosomes, are genetically unstable and are thus dangerous.
Metabolic conversion instead of cell death
A further unwanted effect of the pVHL deficiency: aneuploid cells do not die. If the molecule precipitates, these cells even switch over to a very efficient mode of energy production. They divide more vigorously, grow exuberantly and form cysts, which are considered as precoursor states of tumours. "80 per cent of the tumours in human cells have an abnormal number of chromosomes", states Wilhelm Krek, Professor of Cell Biology.
The loss of pVHL is in part hereditary due to mutations of the gene. There are two copies of the VHL gene. If one copy is already defective at birth, it only needs a mutation or a blockade of the second copy, for cells to no longer produce pVHL.
Medicine against degenerate cells?
Krek is convinced that the new findings on the role of pVHL have a therapeutic use. The greatest chance of success is probably in the fight against aneuploid cells. According to the ETH professor they now need to find a drug which kills them preferentially. Kidney cancer is considered as an aggressive type of cancer, since it often forms offshoots, so-called metastasis. 60 per cent of all patients, who get it, die 5 to 8 years after the treatment, because of the development of metastases, which can no longer be combatted.
Why pVHL plays such an important role only in the kidney cells, with the emergence of degenerate cells, is still unclear, because both the spindle apparatus and the protein is present in all body cells during cell division.
Cell procedures observed in real time
The work developed in a co-operation between cell biologists and biochemists, where the original authors of the paper, which was published in "Nature Cell Biology", by chance exchanged views concerning their own special fields and discovered the close link between pVHL and cell division. Thanks to "Single Cell Life Imaging", a special optical microscope technology, the researchers could observe and follow living cells individually. The Light Microscopy Centre of the ETH Zurich, which offers the technology, is at the forefront of this technology.
Thoma CR et al. VHL loss causes spindle misorientation and chromosome instability. Nature Cell Biology. Nature Cell Biology 11, 994-1001 (2009). Published online 20 July 2009; DOI: 10.1038/ncb1912