p53 Turns Thirty


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(l-r) Dr. Perry Stambolsky and Profs. Varda Rotter and Moshe Oren
In 1979, disco was reaching  its height, Egypt and Israel were negotiating a peace treaty, and cancer researchers were in the midst of the revelation that genes can promote cancer. Certain viruses, for instance those that insert their DNA into the genes of their host cells and others that “borrow” host genes and manipulate them, were found to cause cancer. Almost accidentally, several research groups noted the existence of a gene that seemed to play a role in the cell’s switch to malignancy after becoming infected with  cancer-causing viruses.

Two young Israeli researchers working in the US became involved with the new gene, called p53. (The number refers to the molecular weight. It has since been corrected to 43.7, but the name has stuck.) Moshe Oren was in the Princeton lab of Prof. Arnold Levine – one of those labs that first published the discovery of p53. Meanwhile, Varda Rotter, under the guidance of Nobel laureate Prof. David Baltimore, identified the p53 gene in a different type of virus-caused tumor.
That early research seemed to indicate that p53 was an oncogene – a cancer-causing gene. Rotter’s research in Baltimore’s lab revealed high levels of the p53 protein in many types of cancer cells (including those not infected with a virus), but almost none in non-cancerous ones.
Oren and Rotter both returned to Israel in 1981, soon setting up independent labs in what would become the Weizmann Institute’s Molecular Cell Biology Department, and they began to study the gene in earnest. Quantities of DNA were needed for experiments, and this meant that the gene had to be cloned – a procedure that in those days required, says Oren, “a lot of improvisation, ingenuity and (not least) good luck.” Oren, beginning his work in the lab of Prof. David Givol and continuing to collaborate with Levine, was the first to clone the p53 gene, in 1983. Givol has since joined the circle of p53 researchers, with numerous contributions of his own. Rotter, continuing the work she started in the US, developed new methods for detecting p53 in cells – methods that are in use today in hundreds of labs around the world. In 1983, she suggested that the p53 protein can be regarded as a “tumor-specific marker.”
The two scientists enjoyed a sort of “friendly, constructive competition.” In that first decade p53 research began to take some interesting twists and turns. Sometimes the gene clearly played a role in cancer, but in other cancer cells it was inactivated, and results from different clones didn’t always match. In 1989, Oren, Rotter and others compared the various p53 clones and discovered they were all different; what they had thought were oncogenes were in fact mutated versions of a gene that in healthy cells normally plays an entirely different role.
It soon became apparent that unmutated, healthy p53 is the opposite of a cancer gene – it’s a tumor suppressor that prevents renegade genes from driving the cell toward cancer. Sir David Lane, one of p53’s codiscoverers, dubbed it “the guardian of the genome.” Just as significant were discoveries that p53 is mutated in about half of all cancers and its actions stymied in many others. With that, p53 research took off. But just when it seemed that this one gene might hold the answer to how cancer develops, scientists began to discover how many complex roles that gene can play. To date, over 50,000 scientific papers have been published on p53, and the flow of new discoveries has by no means abated.
While the research of Profs. Oren and Rotter diverged – he turned more to unraveling the role of unmutated p53 in healthy cellular function, she to investigating mutated p53 in cancer – they also began to collaborate. To date, they have published 15 joint papers (see box). They have received numerous awards for their pioneering work, and each of them was recently honored with an invitation to contribute to a special issue of Nature Reviews: Cancer, commemorating 30 years of p53 research.
Was it worthwhile for one small institute to support two groups conducting cutting-edge studies on the same gene? Oren and Rotter say the synergy between them has generated a critical mass that has put the Weizmann Institute and Israel at the forefront of p53 research. They emphasize that at least 20 Weizmann research teams are involved in p53-related research; and the younger generation of scientists is using new methods to address as yet unanswered questions. Indeed, there is hardly a cancer researcher around who hasn’t investigated p53 in one way or another.
Prof. Moshe Oren’s research is supported by the M.D. Moross Institute for Cancer Research.
Prof. Varda Rotter’s research is supported by the Leir Charitable Foundations; the Centre Leon Berard Lyon; the Lombroso Prize for Cancer Research; the Jeanne and Joseph Nissim Family Foundation for Life Sciences; the estate of John M. Lang; and Donald Schwarz, Sherman Oaks, CA. Prof. Rotter is the incumbent of the Norman and Helen Asher Chair of Cancer Research.

When to Skip the Vitamins

Vitamin D may have cancer-prevention properties. But can it help if a person is already ill? Clinical trials examining the effects of vitamin D on patients receiving chemotherapy have not yet answered this question. But Profs. Oren and Rotter’s latest collaborative effort, conducted with former student Perry Stambolsky, began from a different angle altogether: Two unrelated experiments in their labs seemed to point to a connection between p53 and the molecular machinery mediating the cell’s response to vitamin D. Probing further, they found out exactly how this machinery interacts with p53, providing a sort of booster that reinforces its actions. That’s good news when the p53 is a non-mutated tumor suppressor: Vitamin D can assist in destroying the tumor. It might, however, be a reason for concern when p53 is mutated. Oren: “When healthy, p53 prevents cancer. But mutations are like sticks jamming the machinery that keeps cancer at bay, and vitamin D may wedge those ‘sticks’ into the works a little tighter.” Rotter: “When deciding whether to prescribe vitamin D, it might be important to know not just whether the p53 is mutated, but the nature of those mutations.”