Our major goal is to understand how mRNA levels for the proto-oncogene c- myc are regulated, because sustained synthesis of c-myc protein favors cell growth rather than differentiation, a hallmark of the neoplastic phenotype. Many proto-oncogene mRNAs exhibit extremely short half lives. The turnover of these mRNAs is frequently subject to regulatory control. For example, the decay rates of the mRNA for the proto-oncogene c-myc vary during cell growth and differentiation. As a result, c-myc mRNA levels are highest during cell growth and lowest during differentiation. Thus the control of c-myc mRNA decay rates is an important mechanism regulating c-myc expression in mammalian cells. We are interested in why c-myc mRNA is degraded at different rates, how c-myc mRNA turnover is regulated and what factors are involved in its regulation. We developed a cell-free mRNA decay system in order to biochemically dissect the mRNA degradation machinery. Using the cell-free system, we have identified a cytosolic ribonucleoprotein (RNP) which destabilizes c-myc mRNA without affecting mRNA metabolism in general. Its activity varies in extracts from cells depending on cellular rates of translation, growth and stage of differentiation and correlates with the in vivo decay rate of c-myc mRNA. We plan to address the following questions: (1) What is the polypeptide and RNA composition of the RNP? (2) Does it regulate the turnover of other mRNAs beside c-myc? What is the substrate specificity of the RNP? (3) Do changes in c-myc mRNA decay rates, induced by changes in translation, cell growth or differentiation, correlate with quantitative or qualitative changes in the RNP? Our approach is to purify the RNP to determine its composition and mRNA substrate specificity in order to understand its role in c-myc expression.

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National Cancer Institute (NCI)
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Molecular Biology Study Section (MBY)
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Wake Forest University Health Sciences
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Lin, Hsin-Ching; Simon, Peter J; Ysla, Riza M et al. (2017) RNA stability regulates human T cell leukemia virus type 1 gene expression in chronically-infected CD4 T cells. Virology 508:7-17
Li, Mei-Ling; Weng, Kuo-Feng; Shih, Shin-Ru et al. (2016) The evolving world of small RNAs from RNA viruses. Wiley Interdiscip Rev RNA 7:575-88
Lin, Jing-Yi; Brewer, Gary; Li, Mei-Ling (2015) HuR and Ago2 Bind the Internal Ribosome Entry Site of Enterovirus 71 and Promote Virus Translation and Replication. PLoS One 10:e0140291
Lin, Jing-Yi; Li, Mei-Ling; Brewer, Gary (2014) mRNA decay factor AUF1 binds the internal ribosomal entry site of enterovirus 71 and inhibits virus replication. PLoS One 9:e103827
Kishor, Aparna; Tandukar, Bishal; Ly, Yann V et al. (2013) Hsp70 is a novel posttranscriptional regulator of gene expression that binds and stabilizes selected mRNAs containing AU-rich elements. Mol Cell Biol 33:71-84
White, Elizabeth J F; Brewer, Gary; Wilson, Gerald M (2013) Post-transcriptional control of gene expression by AUF1: mechanisms, physiological targets, and regulation. Biochim Biophys Acta 1829:680-8
Li, Mei-Ling; Defren, Jennifer; Brewer, Gary (2013) Hsp27 and F-box protein ýý-TrCP promote degradation of mRNA decay factor AUF1. Mol Cell Biol 33:2315-26
Wu, Xiangyue; Chesoni, Sandra; Rondeau, Gaelle et al. (2013) Combinatorial mRNA binding by AUF1 and Argonaute 2 controls decay of selected target mRNAs. Nucleic Acids Res 41:2644-58
Qi, Mei-Yan; Wang, Zhi-Zhang; Zhang, Zhuo et al. (2012) AU-rich-element-dependent translation repression requires the cooperation of tristetraprolin and RCK/P54. Mol Cell Biol 32:913-28
Xin, Hong; Brown, Julie A; Gong, Changning et al. (2012) Association of the von Hippel-Lindau protein with AUF1 and posttranscriptional regulation of VEGFA mRNA. Mol Cancer Res 10:108-20

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