As a tumor suppressor pulls double shift Reprogramming Watchdog

“Unfortunately, Klf4 and c-Myc are oncogenes and adding them carries the risk of inducing cancer,” says Belmonte. Yet, despite the extra effort provided by these powerful oncogenes, only a small fraction transmogrifies into iPSCs that look and behave like embryonic stem cells, which leads one to wonder if what they were doing Belmonte for reprogramming cells induces a response that is the ‘order of the cells to grow?And, of course, of experiences by postdoctoral researchers and co-first author Teruhisa Kawamura, Ph.D., and Jotaro Suzuki, Ph.D., found that the addition of reprogramming factors c-Myc and Klf4 , alone or in various combinations activated the p53 path. As a first surgery, the tumor suppressor p53 is called into action when cells are under stress. Depending on the situation, p53 then turns on genes that block cell division to allow time for repairs or when all rescue attempts prove futile, for the cell to stop dividing indefinitely, or committing suicide.

In cells genetically modified to lack p53, reprogramming efficiency was at least 10 times higher compared to control cells, demonstrating that p53 clearly played an important role in cells that reigns in an attempt to return to a state like strains.

“There was an old idea of ​​a decade that cancer arises from the dedifferentiation of specialized cells and fully committed, but was ultimately rejected in favor of the theory of cancer stem cells currently in fashion,” says Wahl. “Now that we know that p53 prevents de-differentiation, I think it is time to reconsider the possibility that reprogramming plays a role in cancer development since almost all cancer cells lose p53 function in one way or another. ”

“This successful partnership is an excellent example of what makes the Salk a special place,” says Wahl. “Juan Carlos and I talk every day and we approach the same problem from very different angles. It comes from a standpoint of developmental biology, while I am on the side of cancer, but when put together, can make a big story.”

A conversation with his neighbor, cancer expert Wahl provided some new ideas that could be tested in the laboratory. “Normally, cells do not reprogram so there must be a mechanism in place that prevents,” said Wahl. “We knew that c-Myc and some of the other genes that are necessary to allow the reprogramming of tumor suppressor p53 and we wondered if he had a part.”

This work was supported by the National Institutes of Health, grants from Tercel, Marathus, Harold G. And Leila Y. Mathers Charitable Foundation and Fundacion Cellex.

A joint study by researchers at the Salk Institute for Biological Studies have found that p53, which made his name as “guardian of the genome”, not only stops cells that could become cancerous in their tracks but also controls the reprogramming of somatic cells.

Researcher who has contributed to the work include Yunyuan V. Wang, Ph.D. in the laboratory Wahl, Sergio Menendez, Ph.D., Laura Morera Batlle, Ph.D., and Angel Raya, Ph.D., all at the Center for Regenerative Medicine in Barcelona, ​​Spain .

Their findings bring iPSCs technology a step closer to its promise as a source of patient-specific stem cells, but also force scientists to rethink the development of cancer.

Because iPSCs generated with the complete list of reprogramming factors run the risk of malignant transformation, Belmonte and his team wanted to know if mouse cells lacking p53 could be reprogrammed using only two factors, Oct4 and Sox2. The cells readily converted into iPSCs and gave life to health, term that mice were able to play pass the final test for pluripotent embryonic stem cells.

As mammalian embryos transition through a series of stages of development, the selection of embryonic stem cells, which have almost unlimited prospects are gradually restricted to the end result in about 200 types of cells the body and generally do not have the opportunity to return to a less specialized stage.

Although differentiation is generally irreversible, scientists have developed several methods to overcome the reluctance of the cells to be reprogrammed. The technology used involves the forced expression of four transcription factors Oct4, Sox2, Klf4, and c-Myc in adult cells fully engaged.

Although scientists have learned to reprogram adult cells such as human skin cells into so-called induced pluripotent stem cells (IPSC), the efficiency of reprogramming is still woefully low. The Salk study, published in Nature advance online on August 9, provides new clues to which only a small number of cells of many can be persuaded to go back.

“Although we were able to reprogram specialized cells for some time, nothing was known about the control mechanisms that prevent it from happening spontaneously in the body and why it was so difficult to change their fate in a Petri dish , “says Juan-Carlos Izpis one, Belmonte, Ph.D., professor in the Gene Expression Laboratory, who worked closely with Geoffrey M. Wahl, Ph.D., a professor at the Laboratory of Gene Expression.