Schematic description of the controls in cell proliferation Full size image available through contact |
Under normal conditions, an alteration detected at any of these checkpoints results in the immediate destruction of the cell (see Figure 1) Such a complex mechanism can fail either if cell starts the division without an external signal and any of the checkpoints fail to detect the error, or if the mechanisms designed to delete the abnormal cell fail. For this reason, virtually all of the proteins implicated in these processes can, when altered, be the cause of cancer. They are then called protooncogenes in their normal form, and oncogenes in their altered manifestation. This alteration can be caused by a mutation of the protein itself, inducing a greater activity in those genes implicated in growth stimulation or a decreased activity in those implicated in cell death. Alternatively, the regulation of the expression of the protein can be altered. The expression (conversion of information from the gene into a functional protein) of every gene is tightly regulated and varies depending on many factors, such as the developmental stage of a particular cell, its location and its type. A protein is expressed only where and when it is needed. The expression out of time or out of place results in an altered function, although the structure of the protein can be normal. It is easy to imagine that, since all cells have to divide and eventually die sooner or later, the presence of the proteins implicated in cell cycle control is universal in all tissues.
In contrast to most known oncogenes, the gene discovered at the MPI in Göttingen is not ubiquitous, but expressed in brain under normal conditions.This would offer the possibility to design a diagnostic method to detect a potential cancer by measuring the presence of EAG outside its normal location.
Difference in the volume of tumors implanted subcutaneously into immune-deficient mice. Two million CHO cells expressing either Kv1.4 potassium channels (Control) or EAG were injected into the flank of the mice and allowed to grow for two weeks. Full size image available through contact |
The ion channel with this property carries the name of a mutant of the fruit fly (Drosophila melanogaster) in which a defect in the channel protein causes the flies to rhythmically move under ether: Ether-à-go-go (EAG). The equivalent rat and human genes (rEAG and hEAG) are abundantly expressed in brain where they act as voltage-dependent potassium channels: membrane proteins that regulate the passage of potassium ions through the plasma membrane upon changes in membrane potential. Therefore, they are essential elements contributing to the electrical excitability in nervous tissue. In mammalians, however, these channels seem to be additionally able to increase cell proliferation when expressed outside of the nervous system.
The detection of this ion channel outside of the nervous system and/or out of time is hence a marker for malignant transformation (cancer). In fact, several cell lines derived from human tumors express the hEAG channel, whereas the respective normal tissue does not. Cells that have been genetically modified to express EAG proliferate in the absence of growth factors that are necessary for normal cell proliferation. This means that EAG allows these cells to multiply in the absence of signals telling them to do so. It is important to add that the effects of excessive expression of EAG can also be detected in vivo, in mice carrying tumors that have been manipulated to express EAG (Figure 2).
Once cancer has established, many cell functions are altered and the expression of many genes loose their regulation. A crucial step in the definition of an oncogene is thus the demonstration of a causal link between the presence of the gene and the abnormal growth. The results obtained indicate that the specific blockade of EAG expression causes a reduction in the proliferation rate of cancer cells expressing this specific ion channel. Traditionally, most of the drugs used to treat cancer have many undesired side effects, because they are targeted at actively growing cells, which are not only the tumor cells, but also cells of the intestinal epithelium, cells producing blood components, or cells in the hair follicles. If the results obtained in Dr. Stühmer's laboratory are extrapolatable to a sufficient number of human cancers, EAG would be an ideal target for a therapeutic strategy, because the normal cells expressing this protein are located in the nervous system and well protected by the blood-brain barrier. This means that a drug designed against EAG would not affect the normal function of cells, but only those growing in the tumor.
Published: 15-10-99
Contact: Luis A. Pardo
Max Planck Institute for Experimental Medicine,
Göettingen/Germany
Phone: 49-551-3899-643