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let-7 MicroRNA: A Master Regulator of Cellular Differentiation

Katya Melnik-Martinez

Appointment Period: 2008-2010 / Grant Years: [24,25]

Katya Melnik-MartinezThe discovery that reduced expression of the let-7 miRNA in human lung cancers was associated with poor prognosis sparked a series of studies that led to the conclusion that this highly conserved miRNA has an important tumor suppressor role. In addition to lung cancer, let-7 has also been associated with many other types of cancers. This miRNA regulates multiple genes that promote cellular division or block differentiation. The let-7 miRNA was originally discovered as a gene in the laboratory animal C. elegans that is required for terminal differentiation of several cell types. Mutation of the let-7 gene in this model organism results in inappropriate cellular division, which is likely related to the cellular proliferation phenotype of human tumors that lose let-7 expression. Mutation or loss of let-7 expression results in inappropriate expression of these genes and their downstream targets, which then manifests in abnormal proliferation. I have used genomic, genetic and molecular assays to identify new targets of let-7 that are important for mediating the cellular over-proliferation phenotypes of let-7 mutants.

Additionally, I developed a novel screen to gain insight as to why let-7 levels decrease in many diverse types of cancer cells. Lin-28, a gene important for stem cell and transformed cell fates, negatively regulates let-7 expression in worms and humans. I am using lin-28 mutant worms in a high throughput genome wide RNAi screen to identify factors that influence let-7 regulation by lin-28

Yeh E, Ng S, Zhang M, Bouhours M, Wang Y, Wang M, Hung W, Aoyagi K, Melnik-Martinez K, Li M, Liu F, Schafer WR, Zhen M. A putative cation channel,NCA-1, and a novel protein, UNC-80, transmit neuronal activity in C. elegans. PLoS Biol. (2008) 6:e55. PMID: 18336069; PMC2265767.

Godshalk SE*, Melnik-Martinez KV*, Pasquinelli AE, Slack FJ. MicroRNAs and cancer: a meeting summary of the eponymous Keystone Conference. Epigenetics. (2010) 5:164-8. PMID: 20168081. *Co-first authors

Hunter S, Finnegan E, Zisoulis DG, Kai ZS, Zisoulis, Melnik-Martinez KV, Pasquinelli AE, A network of let-7 targets regulates cellular differentiation in C. elegans. (2012) In preparation.