Resisting Division


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Professors: Yosef Yarden,Moshe Oren and Eytan Domany

Temptations to exceed the speed limit are always plentiful, but only reckless drivers give in to such impulses. Likewise, numerous growth factors always abound in our bodies, but only cancerous cells are quickly “tempted” by these chemicals to divide again and again. Healthy cells, in contrast, divide only after being exposed to growth factors for eight continuous hours. What happens during these eight hours in a healthy cell that resists the call to divide? And even more important, what fails to work properly in the cancer cell during these same hours? Why do cancerous cells give in so easily to the influence of growth factors and divide so readily?

Answers to these questions have emerged from a study by a multidisciplinary team of Weizmann Institute researchers published recently in Molecular Cell. The scientists found that when a cell first receives a signal from a growth factor, ten groups of genes – about 8,000 in total – become activated. Of these, one group, consisting of about ten genes governed by the tumor suppressor p53, is the most crucial: These genes prevent the cell from dividing. Only if the growth factor continues to affect the cell for eight hours does p53 release its grip on the cell’s DNA, allowing it to divide. Like a careful driver who puts the brakes on before proceeding, the activation of p53 at the time the cell receives a growth factor signal serves as a “brake,” preventing instant division. In this manner, the healthy cell ensures that it will not divide as a result of accidental, mistaken or otherwise superfluous growth signals, but only if the signal is continuous and necessary. In cancerous cells, this mechanism malfunctions because in most of them p53 is defective or missing altogether, so that even a fleeting growth signal can cause them to divide, leading to cancerous growth.

This interdisciplinary study has resulted from a collaboration between three research teams at the Weizmann Institute, headed by Prof. Yosef Yarden of the Biological Regulation Department, Prof. Eytan Domany of the Physics of Complex Systems Department and Prof. Moshe Oren of the Molecular Cell Biology Department. The study was coordinated by former graduate student Dr. Yaara Zwang. Other Weizmann scientists taking part were Aldema Sas-Chen, Yotam Drier, Dr. Tal Shay, Roi Avraham, Dr. Mattia Lauriola, Efrat Shema and Efrat Lidor-Nili. Additional participants were clinical researchers Dr. Jasmine Jacob-Hirsch, Dr. Ninette Amariglio and Prof. Gideon Rechavi of the Chaim Sheba Medical Center; and Drs. Yiilng Lu and Gordon B. Mills of the M.D. Anderson Cancer Center at the University of Texas.
Genes that delay cell division exhibit reduced levels of expression (left) after exposure to a second, delayed pulse of growth factor. Those in cells receiving a single pulse (right box) maintained high expression levels

This research sheds new light on the differences between healthy and cancerous cells. It might contribute to the development of new, effective approaches to chemotherapy. Cancerous tumors sometimes develop resistance to the therapy because, among other reasons, it stresses the body, which in turn, leads to the production of growth factors that cause cells to divide. The treatment thus ultimately defeats itself. A better understanding of how growth factors work can help determine intervals for administering chemotherapy that will prevent the rampant division of cancerous cells.
Prof. Eytan Domany's research is supported by the Kahn Family Research Center for Systems Biology of the Human Cell; the Mario Negri Institute for Pharmacological Research - Weizmann Institute of Science Exchange Program; the Leir Charitable Foundation; and Mordechai Segal, Israel.  Prof. Domany is the incumbent of the Henry J. Leir Professorial Chair.
Prof. Moshe Oren's research is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the Robert Bosch Foundation; and the estate of Harold Z. Novak.  Prof. Oren is the incumbent of the Andre Lwoff Professorial Chair in Molecular Biology.
Prof. Yosef Yarden's research is supported by the M.D. Moross Institute for Cancer Research; the Aharon Katzir-Katchalsky Center, which he heads; the Kekst Family Institute for Medical Genetics; the Kirk Center for Childhood Cancer and Immunological Disorders; the Women's Health Research Center funded by the Bennett-Pritzker Endowment Fund, the Marvelle Koffler Program for Breast Cancer Research, the  Harry and Jeanette Weinberg Women's Health Research Endowment, and the Oprah Winfrey Biomedical Research Fund; the Steven and Beverly Rubenstein Charitable Foundation , Inc.; Julie Charbonneau, Canada; the Jean - Jacques Brunschwig Fund for the Molecular Genetics of Cancer; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the Centre Leon Berard - Lyon; the Laub Fund for Oncogene Research; the estate of Norman Davis; and the Marvin Tanner Laboratory for Research on Cancer. Prof. Yarden is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology.