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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM081686-06
Application #
8805478
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Gaillard, Shawn R
Project Start
2008-07-01
Project End
2014-06-30
Budget Start
2013-08-01
Budget End
2014-06-30
Support Year
Fiscal Year
2013
Total Cost
$236,772
Indirect Cost
$83,024
Name
University of California Los Angeles
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Mitra, Mithun; Johnson, Elizabeth L; Coller, Hilary A (2015) Alternative polyadenylation can regulate post-translational membrane localization. Trends Cell Mol Biol 10:37-47
Corney, David C; Coller, Hilary A (2014) On form and function: does chromatin packing regulate the cell cycle? Physiol Genomics 46:191-4
Jiang, Peng; Singh, Mona; Coller, Hilary A (2013) Computational assessment of the cooperativity between RNA binding proteins and MicroRNAs in Transcript Decay. PLoS Comput Biol 9:e1003075
Evertts, Adam G; Manning, Amity L; Wang, Xin et al. (2013) H4K20 methylation regulates quiescence and chromatin compaction. Mol Biol Cell 24:3025-37
Jiang, Peng; Coller, Hilary (2012) Functional interactions between microRNAs and RNA binding proteins. Microrna 1:70-9
Suh, Eric J; Remillard, Matthew Y; Legesse-Miller, Aster et al. (2012) A microRNA network regulates proliferative timing and extracellular matrix synthesis during cellular quiescence in fibroblasts. Genome Biol 13:R121
Waldron, Levi; Coller, Hilary A; Huttenhower, Curtis (2012) Integrative approaches for microarray data analysis. Methods Mol Biol 802:157-82
Wang, David J; Legesse-Miller, Aster; Johnson, Elizabeth L et al. (2012) Regulation of the let-7a-3 promoter by NF-κB. PLoS One 7:e31240
Ventura-Clapier, Renée; Coller, Hilary A (2012) A step toward systems metabolomics. Physiol Genomics 44:383-5
Coller, Hilary A (2011) Cell biology. The essence of quiescence. Science 334:1074-5

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