Regulator of microRNAs is key to cell reprogramming and carcinogenesis
Could provide target for enhancing stem-cell generation or inhibiting cancer
February 21, 2008
MicroRNAs are a recently discovered class of RNAs that encode no proteins but instead regulate gene activity. Researchers at Children's Hospital Boston and the Harvard Stem Cell Institute have discovered the first protein to block the processing of immature microRNAs in cells to mature forms. Drugs that target this protein, known as Lin-28, have the potential to influence the creation of stem cells and provide a new approach to treating some cancers, the authors say.
The discovery, reported online February 21 in ScienceExpress, "provides a key insight into two fundamental processes in biology--stem cell generation and carcinogenesis," says Richard Gregory, PhD, the study's senior author.
Lin-28 regulates the let-7 family of microRNAs, known to be key players in cancers of the lung and breast, and was also recently shown to help reprogram skin cells to pluripotent stem cells resembling embryonic stem cells. Because both cellular reprogramming and carcinogenesis entail cellular de-differentiation (reversion of a mature cell to a less mature state), Lin-28 provides a missing link between stem cell generation and cancer.
Richard Gregory, PhD"We are actively seeking drugs that mimic or block the effect of Lin-28 on microRNAs, as these drugs will either enhance stem cell generation, or inhibit cancers, respectively," says Gregory.
In 2006, Scott Hammond's group at University of North Carolina, Chapel Hill, discovered that microRNAs were made as immature forms in embryonic cells and cancer cells, but the mechanism for the blocking of their maturation remained elusive. Srini Viswanathan, a graduate student in the laboratory of George Daley, MD, PhD, at Children's Hospital Boston, was interested in how microRNAs might dictate tissue formation from embryonic stem cells, which show a block in processing of a specific family of microRNAs called let-7.
Viswanathan and Gregory hypothesized that some protein must bind to the immature form of let-7 microRNAs to block their processing, and set out to purify the protein. They identified a number of proteins associated with microRNAs, but only Lin-28 was uniquely expressed in embryonic tissues. They then demonstrated that Lin-28 was directly responsible for the blockade of let-7 microRNA in embryonic cells: expressing Lin-28 in non-embryonic cells reproduced the block in let-7 processing, and inhibiting Lin-28 expression in embryonic tissues caused upregulation of let-7.
Unbeknownst to the Children's researchers, Lin-28 was being studied by James Thomson's group at the University of Wisconsin as a factor that enhanced reprogramming of skin cells back to an embryonic state. Thomson's paper (published while the Children's paper was under review) did not provide an explanation for how Lin-28 could contribute to stem cell generation. "Our study helps explain how Lin-28 works--by blocking microRNAs that promote cell differentiation," says Daley.
The study also provides a key insight into cancer. A characteristic of cancer is low expression of microRNAs. In their paper, Viswanathan, Daley and Gregory show that a close relative of Lin-28, Lin-28b, which has been linked to hepatocellular carcinoma, likewise blocks processing of let-7 microRNAs. Loss of the let-7 microRNA is critical for breast and lung cancer. Therefore, the study suggests that activating Lin-28 may promote cancer formation, whereas blocking it may be protective, the researchers say.
"The discovery of how Lin-28 works was an unexpected 'Eureka' moment," says Viswanathan. "We are looking forward to finding drugs that antagonize Lin-28, as these might be an important weapon against cancer."
The research was funded by Children's Hospital Boston, The Harvard Stem Cell Institute, and the NIH Director's Pioneer Award of the NIH Director's Roadmap for Medical Research.
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 12 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 397-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: www.childrenshospital.org/newsroom.
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