The discovery of the tumor suppressor gene p53

How does it happen that a cell suddenly divides infinitely, its growth gets out of control and it becomes the "internal enemy" of organisms? According to recent findings in human and mammalian genetics, malignant tumors arise when genes that regulate growth spontaneously change. In this process, genes that fight cell proliferation (tumor suppressor genes) as well as those that stimulate cell proliferation (oncogenes) can mutate. If both types of genes are disturbed in their function, uncontrolled cell division can lead to malignant tumors.

The role that certain genes play in the development of cancer was explored by the winners of the Paul Ehrlich and Ludwig Darmstaedter Prize 1998. Professors David Lane (University of Dundee/Scotland), Arnold Levine (Princeton University/New Jersey) and Bert Vogelstein (Johns Hopkins Oncology Center/, Baltimore, Maryland) receive the most important medical prize in Germany for their research on the p53 gene, a gene named after the size of its protein product. The Paul Ehrlich and Ludwig Darmstaedter Prize, whose prize money will be increased in 1998 for the first time from previously 90,000 DM to 120,000 DM, is awarded annually on Paul Ehrlich's birthday, 14 March, in the Paulskirche in Frankfurt.

When microoncologist David Lane and microbiologist Arnold Levine independently isolated the p53 gene in 1979, it was initially thought to be a cancer-causing gene (oncogene). However, it later became clear that this property was due to a mutation. Unmodified p53 has exactly the opposite effect. It protects the cell from uncontrolled growth. When a mutation occurs in the cell, normally p53 is produced, which prevents cell division. This gives the cell time to repair the damage. If it fails to do so, p53 activates a mechanism that kills the cell. For this reason, p53 has also been given the name "guardian angel" among scientists. However, an altered p53 loses this protective function: cells with an oncogenetic mutation are not killed and grow uncontrollably. Numerous studies have shown that p53 is the most frequently mutated gene in human tumors; about 50 percent of all tumors have a p53 mutation.

At the end of the 1980s, the oncologist Bert Vogelstein demonstrated that a mutation alone is by no means sufficient to trigger abnormal cell growth. Exploring the development of colon cancer, Vogelstein and his research group showed that only an accumulation of genetic changes in oncogenes and tumor suppressor genes, including p53, leads to extremely malignant forms of colon cancer.

As a consequence of these discoveries p53 is becoming a focus of research. Since it is known that conventional anticancer drugs destroy mutated cells by activating the p53-dependent self-dissolution mechanism of apoptosis, restoring the original function of p53 appears to be a promising strategy for an improved cancer therapy. Moreover, cancer therapy takes advantage of the genetic differences between normal and mutant p53 in selectively destroying tumor cells.

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