The Sept4 Gene Prevents Stem Cells From Turning Cancerous


Stem cells, those prodigious precursors of all the tissues in our body, can make almost anything, given the right circumstances, but unfortunately that can also cause cancer sometimes. However research from Rockefeller University has shown that having too many stem cells, or stem cells that live too long, can increase the odds of developing cancer. By identifying a mechanism that regulates programmed cell death in precursor cells for blood, or the stem cells that make all blood-based cells (hematopoietic stem cells), these researchers have connected the death of such cells to a later susceptibility to develop tumors in mice. This work also provides evidence of the potentially carcinogenic downside to stem cell treatments, and suggests that there is a balance between stem cells’ regenerative power and their potentially lethality.
Research associate Maria Garcia-Fernandez and head of the Strang Laboratory of Apoptosis and Cancer Biology, Hermann Steller, and colleagues explored the activity of a gene called Sept4. Sept4 encodes a protein called ARTS that increases programmed cell death, or apoptosis, by antagonizing other proteins that prevent cell death. ARTS was originally discovered by Sarit Larisch while visiting Rockefeller, and is lacking in human leukemia and other cancers, which suggests that it suppresses tumors. To study the role of ARTS, the experimenters bred a line of mice genetically engineered to lack the Sept4 gene.
For several years, Garcia-Fernandez studied cells that lacked ARTS. He goal was to look for signs of trouble relating to cell death. However, in mature B and T cells, she could not find any. Then when she examined these cells at earlier and earlier times in their development she found crucial differences between the stem cells that gave birth to the progenitor cells that eventually became the mature B and T cells and the stem cells themselves. Newborn ARTS-deprived mice had about twice as many hematopoietic stem cells as their normal, ARTS-endowed peers. Furthermore, these stem cells were extraordinary in their ability to survive experimentally induced mutations. “The increase in the number of hematopoietic progenitor and stem cells in Sept4-deficient mice brings with it the possibility of accelerating the accumulation of mutations in stem cells,” says Garcia-Fernandez. “They have more stem cells with enhanced resistance to apoptosis. In the end, that leads to more cells accumulating mutations that cannot be eliminated.”
In fact the ARTS-deprived mice developed spontaneous tumors at about twice the rate of their controls. Herman Steller said, “We make a connection between apoptosis, stem cells and cancer that has not been made in this way before: this pathway is critically important in stem cell death and in reducing tumor risk…. The work supports the idea that the stem cell is the seed of the tumor and that the transition from a normal stem cell to a cancer stem cell involves increased resistance to apoptosis.”
ARTS interferes with molecules called inhibitor of apoptosis proteins (IAPs), which prevent cells from undergoing programmed cell death. When cells accumulate too much damage to work properly, programmed cell death ensues, and the damaged cell is replaced by a new cell. Programmed cell death is also called “apoptosis.” By inhibiting these IAPs, under the right circumstances ARTS helps to take the brakes off the process of apoptosis that normally permits the cell to die on schedule. Pharmaceutical companies are working to develop small molecule IAP antagonists, but this research is the first to show that inactivating a natural IAP antagonist actually causes tumors to grow, according to Steller. It also suggests that premature silencing of the Sept4/ARTS pathway at the stem cell level may herald cancer to come.
“This work not only defines the role of the ARTS gene in the underlying mechanism of mammalian tumor cell resistance to programmed cell death, but also links this gene to another hallmark of cancer, stem and progenitor cell proliferation,” said Marion Zatz, who oversees cell death grants, including Steller’s, at the NIH’s National Institute of General Medical Sciences. “The identification of the ARTS gene and its role in cancer cell death provides a potential target for new therapeutic approaches.”

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mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).