Dysregulated expression of the c-MYC proto-oncogene is one of the most frequent abnormalities in human malignancies. Through the control of an expansive target gene network, this transcription factor drives proliferation and, in some settings, induces cell death. Despite great advances in the identification of c-Myc-regulated genes, the mechanisms through which this oncogene promotes tumorigenesis are not yet fully understood. MicroRNAs are ~18-24 nucleotide RNA molecules that have emerged as major regulators of eukaryotic gene expression. We recently identified a group of microRNAs, known as the mir-17 cluster, that are directly upregulated by c-Myc. Independently, these microRNAs were shown to cooperate with c-Myc in promoting tumorigenesis. We have now also identified a cohort of microRNAs that are directly repressed by c-Myc. Many of these are known to be deleted or mutated in cancer, suggesting that they possess tumor suppressor activity. We now propose studies designed to test the hypothesis that these c-Myc-regulated microRNAs are critical components of the c-Myc target gene network that regulate cellular proliferation, apoptosis, and neoplastic transformation.
In Aim 1 of this project, we will investigate the phenotypic consequences of expression or inhibition of the mir-17 cluster in multiple cell types. These experiments are necessary to set the stage for detailed molecular analyses of the mechanisms through which these microRNAs influence oncogenic phenotypes. We will begin to investigate these mechanisms in the latter part of this aim, where the hypothesis that the mir-17 cluster influences cell-cycle control through regulation of p21WAF1 is tested.
In Aim 2, we will continue to dissect the mechanisms through which the mir-17 cluster influences cellular phenotypes. Here, we will test the hypothesis that the mir-17 cluster participates in a physiologic negative-feedback circuit that maintains tightly-controlled expression of c-Myc and other Myc family members in non-transformed cells. Finally, in Aim 3, we will investigate the role of microRNA repression in c-Myc-mediated tumorigenesis. MicroRNAs that are directly repressed by c-Myc will be characterized and the consequences of enforced expression of these microRNAs in in vitro and in vivo models of lymphoma will determined. We envision that these experiments will reveal novel regulatory circuitry that functions abnormally in cancer and may ultimately be amenable to therapeutic intervention.
|Golden, Ryan J; Chen, Beibei; Li, Tuo et al. (2017) An Argonaute phosphorylation cycle promotes microRNA-mediated silencing. Nature 542:197-202|
|Kent, Oliver A; Mendell, Joshua T; Rottapel, Robert (2016) Transcriptional Regulation of miR-31 by Oncogenic KRAS Mediates Metastatic Phenotypes by Repressing RASA1. Mol Cancer Res 14:267-77|
|Lee, Sungyul; Kopp, Florian; Chang, Tsung-Cheng et al. (2016) Noncoding RNA NORAD Regulates Genomic Stability by Sequestering PUMILIO Proteins. Cell 164:69-80|
|Chang, Tsung-Cheng; Pertea, Mihaela; Lee, Sungyul et al. (2015) Genome-wide annotation of microRNA primary transcript structures reveals novel regulatory mechanisms. Genome Res 25:1401-9|
|Knabel, Matthew K; Ramachandran, Kalyani; Karhadkar, Sunil et al. (2015) Systemic Delivery of scAAV8-Encoded MiR-29a Ameliorates Hepatic Fibrosis in Carbon Tetrachloride-Treated Mice. PLoS One 10:e0124411|
|Pertea, Mihaela; Pertea, Geo M; Antonescu, Corina M et al. (2015) StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol 33:290-5|
|Huang, Tai-Chung; Renuse, Santosh; Pinto, Sneha et al. (2015) Identification of miR-145 targets through an integrated omics analysis. Mol Biosyst 11:197-207|
|Wu, Linwei; Nguyen, Liem H; Zhou, Kejin et al. (2015) Precise let-7 expression levels balance organ regeneration against tumor suppression. Elife 4:e09431|
|Rakheja, Dinesh; Chen, Kenneth S; Liu, Yangjian et al. (2014) Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis through distinct mechanisms in Wilms tumours. Nat Commun 2:4802|
|Chivukula, Raghu R; Shi, Guanglu; Acharya, Asha et al. (2014) An essential mesenchymal function for miR-143/145 in intestinal epithelial regeneration. Cell 157:1104-16|
Showing the most recent 10 out of 36 publications