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REGULATION OF THE MYCN PROTO-ONCOGENE BY RNA-BINDING PROTEIN HUD AND MICRORNAS IN NEUROBLASTOMA

by
Riza Carmel M. Ysla
B.A., 2003
Rutgers University

Thesis Advisor: Gary Brewer, Ph.D.

Graduate Program in Microbiology and Molecular Genetics

Thursday, February 23, 2012
10:00 am


Abstract

Neuroblastoma, a cancer of the sympathetic nervous system, is one of the most common childhood tumors, accounting for approximately 6-10% of all childhood malignancies. Numerous studies indicate that increased expression of the proto-oncogene MYCN promotes progression of a subset of neuroblastoma tumors. AU-rich elements (AREs) and microRNA recognition elements (MREs) are cis-acting sequences usually located in 3-untranslated regions (UTRs) of numerous mRNAs, and dictate its degradation rate. AU-rich binding proteins (AUBPs) and microRNAs (miRNAs) are trans-acting factors that orchestrate post-transcriptional gene regulation by their interaction with AREs and MREs, respectively. Here we explore the role of potential MREs, recognized by miR-101, in MYCN mRNA stability in neuroblastoma cell lines. Reporter mRNA half-life studies indicate MRE 101 is an instability element. The AUBP, HuD binds to AREs to cause mRNA stabilization. Additionally, immunoprecipitation of native mRNPs revealed miRNA/RNA-Induced Silencing Complex (RISC) association with MYCN mRNA. HuD inhibited RISC association with MYCN, and this stabilized the mRNA. Finally, the effect of HuD on mRNA stabilization required the AREs. Our observations suggest a model where post-transcriptional control of MYCN mRNA is regulated by HuD, which requires the AREs to be present in order to abrogate RISC association and effect mRNA stabilization.


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