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Two fundamental processes in biology—stem cell generation and carcinogenesis—are closely related, though it hasn't been clear how until now. A discovery from Children's Hospital Boston provides the missing link, and suggests new approaches to creating stem cells for therapeutic purposes and to blocking certain cancers.
Front and center is a protein called Lin-28, which is abundant in embryonic stem cells and inhibits them from differentiating into specific cell types. Richard Gregory, PhD, a principal investigator in the Stem Cell Program at Children's, collaborating with graduate student Srinivas Viswanathan from the lab of George Daley, MD, PhD, showed that Lin-28 regulates an important family of microRNAs called Let-7. (MicroRNAs, hotly pursued by biologists, are snippets of genetic code that regulate gene activity.) As the team reported in Science Express in early 2008, increasing a cell's Lin-28 production blocked the production of mature Let-7 microRNAs; conversely, inhibiting Lin-28 production led to an increase in mature Let-7.
Why is this important? Low levels of mature Let-7 microRNA make a cell more prone to de-differentiate—revert to a less mature, unspecialized, stem-like state—and are associated with breast and lung cancer. Notably, de-differentiation is involved in both cellular reprogramming to create pluripotent stem cells (capable of generating all cell types) and in carcinogenesis.
"We are actively seeking both drugs that mimic the effect of Lin-28 on microRNAs to enhance stem cell generation, and drugs that block Lin-28 to inhibit cancers," says Gregory.
Gregory is conducting large-scale chemical screening to find such compounds. He also hopes to find other microRNAs involved in stem-cell self-renewal and differentiation—as well as compounds that target them.
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