Many cells in the human body are quiescent; that is, they have temporarily stopped dividing but retain the capacity to divide when conditions are suitable, for instance, when the organism must grow or a damaged tissue must be repaired. Although quiescence is a common state for many somatic cells, including stem cells, we know remarkably little about the regulation of cellular quiescence, the changes that cells undergo upon becoming quiescent, and what quiescence looks like in the body. We demonstrated that quiescence is an active and evolving state characterized by extensive changes in gene expression patterns. We hypothesized that microRNAs are involved in regulating the large number of gene expression changes observed with quiescence. We identified specific microRNAs up- and down-regulated with quiescence. miR-31 is downregulated with quiescence and is upregulated in colon and pancreatic cancer, especially late stage tumors. We have shown that overexpression of miR-31 results in a faster and more robust cell cycle entry from quiescence. We propose here to identify miR-31 targets and define the mechanisms by which it affects quiescence. We also propose to define the sequences within the miR-31 promoter responsible for its downregulation with quiescence. Only a small number of molecules can hasten cell cycle entry from quiescence, including myc, E2F and cyclin E. We anticipate that elucidating the mechanisms by which miR-31 promotes proliferation will elucidate an important new signaling pathway.
Many common diseases likely result from failures of quiescence; that is, an inability of cells to temporarily stop dividing. These include developmental abnormalities, tumors, fibrosis, and ulcers. The ability to reenter the cell cycle after quiescence is a critical attribute of stem cells, and its decline likely contributes to aging. We propose here to characterize the role of one specific signaling pathway central to quiescence, and expect that the mechanisms identified will provide important insights into a wide range of medical conditions. ? ? ? ?
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