However, as Drs. Donal O'Carroll and Alexander Tarakhovsky (The Rockefeller Institute) report in an upcoming issue of G&D, Ago2's defining characteristic is surprisingly non-essential for its role in hematopoiesis and miRNA biogenesis.
An advanced version of their paper will be posted online at www.genesdev
Drs. O'Carroll, Tarakhovsky and colleagues generated transgenic mice harboring mutated versions of Ago2 in their bone marrow. The researchers found that Ago2 is, indeed, quite necessary for normal blood cell development. Its endonulcease activity, however, is not.
The scientists were able to restore erythropoiesis in Ago2-deficient mice by expressing a mutated version of Ago2 that lacks its endonuclease activity, thereby demonstrating that the role of Ago2 in the hematopoietic system is independent of its slicer activity. Rather, Dr. O'Carroll and colleagues found that Ago2 regulates miRNA biogenesis in blood cells.
"Our results suggest that the effector function of miRNA in somatic cells relies mostly on translational control of gene expression rather than on destruction of the mRNA targets. This finding may force rethinking of current strategies for the identification of miRNA targets in cells with individual miRNA overexpression or deficiency," explains Dr. Tarakhovsky.
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According to Dr. Monga, these results suggest that PDGFR offers an important new therapeutic target for the treatment of HCC.
"We are very excited because this is the first targeted therapy for liver cancer. Other therapies have some modest benefits, but no one knows exactly how they work. We now have identified a pathway that appears to be overly active in more than 70 percent of the cancers we examined and, when targeted, leads to significant reduction in tumor cell proliferation and survival," said Dr. Monga.
More importantly, targeting the PDGFR pathway in liver cancer cells does not appear to affect normal liver cells, making the treatment relatively non-toxic. "Normally, regenerating liver cells are not exclusively dependent on this pathway, and it is not overly active in other types of cells. So this monoclonal antibody is a highly targeted treatment for this disease," he added.
Furthermore, because high expression of PDGFR has been detected in a variety of tumors, such as skin cancer, brain tumors, gastrointestinal tumors, prostate tumors, ovarian cancer and leukemia, Dr. Monga believes these findings could have much broader applications.
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