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Tumor suppressor pulls double shift as reprogramming watchdog
Date:8/9/2009

till they eventually give rise to the roughly 200 cell types that make up our body and generally lack the ability to revert back to a less specialized stage.

Although differentiation is generally irreversible, scientists have developed several methods to overcome the cells' reluctance to be reprogrammed. The most widely used technology involves the forced expression of four transcription factorsOct4, Sox2, Klf4, and c-Mycin fully committed adult cells.

"Unfortunately, Klf4 and c-Myc are oncogenes and adding them carries the risk of inducing cancer," says Belmonte. Yet, despite the extra push provided by those powerful oncogenes, only a tiny fraction transmogrifies into iPSCs that look and act like embryonic stem cells, leading Belmonte to question whether what they were doing to get the cells to reprogram induced a response that stopped the cells from growing?

A conversation with his next-door neighbor, cancer expert Wahl provided some fresh ideas that could be tested in the lab. "Normally, cells don't reprogram so there must be a mechanism in place that prevents it," says Wahl. "We knew that c-Myc and some of the other genes that are required for reprogramming activate the tumor suppressor p53 and we wondered whether it had any part in it."

And sure enough, experiments by postdoctoral researchers and co-first authors Teruhisa Kawamura, Ph.D., and Jotaro Suzuki, Ph.D., revealed that adding the reprogramming factors c-Myc and Klf4, alone or in various combinations activated the p53 pathway. As a first-responder, the tumor suppressor p53 is called to action when cells experience stressful conditions. Depending on the situation, p53 then turns on genes that halt cell division to allow time for repairs or, when all rescue attempts prove futile, order the cell to stop dividing forever or to commit suicide.

In cells genetically engineered to lack p53, reprogramming efficiency was at least 10-fold increased compared to contro
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Contact: Gina Kirchweger
kirchweger@salk.edu
858-453-4100 x1340
Salk Institute
Source:Eurekalert  

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