REHOVOT, Israel - November 13, 1997 -A Weizmann Institute of Science study reported in the November 13 issue of Nature provides new evidence for an intriguing theory about the development of metastasis.
In the new study, Weizmann researchers demonstrate that a cell-suicide gene called DAP-kinase can prevent metastasis. This finding suggests that a loss or malfunction of this gene allows metastasis to develop.
"In our experiment, we have shown that introducing a 'good' copy of DAP-kinase into metastatic cells restores the ability of these cells to follow the order to kill themselves," says research team leader Prof. Adi Kimchi of the Weizmann Institute's Molecular Genetics Department.
"It's important, however, to remember that this gene is only one of many factors involved in the development of metastasis, so that much research still needs to be conducted before we can find molecular ways to block this life-threatening process," she says.
Kimchi conducted the study with doctoral students Boaz Inbal and Ofer Cohen, as well as with Prof. Lea Eisenbach and Ezra Vadai of the Institute's Immunology Department, and Drs. Sylvie Polak-Charcon and Juri Kopolovic of the Sheba Medical Center in Tel Hashomer.
When cells 'refuse' to die
The DAP-kinase gene was discovered and isolated by Prof. Kimchi's team some two years ago. This gene was known to be involved in cell "suicide," also referred to as programmed cell death or apoptosis.
Cell death is essential for the proper renewal and turnover of tissues. But when cells "refuse" to die after they have finished performing their function - for example, because the DAP-kinase gene is lacking or doesn't function properly - the result can be unwanted cell proliferation and development of cancerous tumors.
Prof. Kimchi hypothesized that apart from contributing to the development of primary tumors, the lack or malfunctioning of DAP-kinase can also cause cancerous cells to break off from a tumor and set out to spawn metastases. Formation of metastases is the most dangerous stage in cancer.
Kimchi and colleagues found that in metastatic tumor lines DAP-kinase indeed is not functioning. To test their hypothesis further, they "engineered" DAP-kinase into cells removed from metastatic tumors in mice, and returned these cells into the laboratory animals. The result: the molecular activity that could lead to the formation of metastases ceased inside these cells.
This finding supported the notion that when the cells contain a normal, functioning copy of the DAP-kinase gene, they obey the signals that instruct them to die during the different stages of metastasis.
In contrast, when the gene is not doing its job the cell disobeys the "suicide" command, and this disobedience may result in metastasis.
Prof. Kimchi holds the Helena Rubinstein Chair of Cancer Research, and Prof. Eisenbach, the Georg F. Duckwitz Chair of Cancer Research.
This research was supported by QBI Ltd. and the Israel Ministry of Science.
The Weizmann Institute of Science is a major center of scientific research and graduate study located in Rehovot, Israel.
Shooting The Messenger
The age-old appeal to avoid 'shooting the messenger' is apparently left unheeded by the body's protein regulation system. Researchers at the Weizmann Institute of Science have recently uncovered one of the mechanisms underlying the synthesis and regulation of actin - the most abundant protein in eukaryotic cells. Their findings reveal an intricate autoregulatory system based on destroying actin's messenger RNA.
Actin serves as the central building block of microfilaments - the cytoskeletal fiber system influencing cell shape, division, adhesion, and motility. In turn, these cellular functions control important biological processes, including embryonic development and wound healing. In order to perform these diverse functions effectively, actin levels need to be balanced with clockwork precision. Indeed, faulty actin regulation can have wide-ranging, often devastating effects, including the onset of cancer and blood diseases.
Professor Avri Ben-Ze'ev, together with Prof. Alexander Bershadsky and doctoral student Anna Lyubimova of the Weizmann Institute's Department of Molecular Cell Biology have recently zeroed in on one of the actin regulatory mechanisms. Their findings, published in the November, 1999 issue of the Journal of Cellular Biochemistry, further the understanding of a central question in biology, namely, the interplay between cell shape and structure, and gene expression.
Actin exists in the cell in two states: a monomeric (or single unit) form, and a polymeric state (consisting of a chain of monomeric units). In a previous study, the researchers found that actin synthesis is regulated by the fine balance between these two forms. When in excess, the monomeric actin 'shuts off' its own synthesis by destroying the machinery necessary for its production. It exerts a negative feedback mechanism leading to the degradation of its messenger RNA (which carries the genetic instructions required for its biosynthesis). The researchers unraveled this mechanism by introducing natural substances known to modify the polymeric - monomeric actin balance. These included latrunculin A, derived from a Red Sea sponge (which in nature serves as a potent defense mechanism, exerting a lethal anti-predatory effect by causing actin depolymerization).
Yet how does the monomeric actin monitor and regulate its own levels? Prof. Ben-Ze'ev and his team used a dual intervention strategy in order to pinpoint the precise 'sensor' responsible. They increased the monomeric actin levels (using latrunculin), together with systematically deleting minute parts of the actin encoding mRNA. Their reasoning? They hoped to find which part of the actin gene, when deleted, would prevent the negative feedback system from kicking in.
The researchers found that this form of actin regulation depends on sequences localized in the actin mRNA 3'untranslated region (3'-UTR). 'This region contains a 'zip code' binding site, which apparently triggers actin mRNA degradation when, due to excess monomeric actin levels, actin mRNA overflows into 'unacceptable' parts of the cell,' Ben-Ze'ev explains. Deleting this region led to a dramatic increase in monomeric actin levels, coupled with severe aberrations in cell morphology and the structure of the actin cytoskeleton.
The Weizmann team's discovery of a direct link between regulating the genetic expression of actin mRNA and specific changes in cytoskeletal dynamics, represents a breakthrough in understanding the relationship between gene expression and cell morphogenesis at the molecular level.
Actin's Balancing Act
This study was funded by the Minerva Foundation, the Israel Ministry of Science, and the German-Israeli Foundation for Scientific Research and Development. The generous support of the Yad Abraham Center for Cancer Diagnostics is also acknowledged.
Prof. Avri Ben-Ze'ev holds the Lunenfeld-Kunin Professorial Chair in Genetics and Cell Biology.
The Weizmann Institute of Science is a major center of scientific research and graduate study located in Rehovot, Israel.