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Post-transcriptional control of gene expression in cancer. immune responses. and congestive heart failureRapid mRNA decay results from cis-acting elements present in labile mRNAs. For example. many mRNAs encoding oncoproteins. cytokines. and G protein-coupled receptors are labile due to the presence of A+U-rich elements (AREs) in their 3'-UTRs. We developed and have utilized a cell-free mRNA decay system to biochemically dissect the turnover machinery. Using this system we identified. purified and molecularly cloned an RNA-binding protein. AUF1. which effects ARE-directed mRNA decay via its high-affinity binding to AREs. We have a number of projects ongoing in my lab. (1) We are utilizing the cell-free mRNA decay system to dissect how AUF1-ARE interactions target mRNAs for rapid decay. (2) We are utilizing a cell line deficient in AUF1activity to ectopically express AUF1 and examine the effects on ARE-directed mRNA decay. (3) AUF1 levels are elevated in hearts of patients with congestive heart failure compared to normal hearts. By contrast. the levels of ß1-adrenergic receptor (ß1AR) mRNA. which contains an ARE. and protein are lower in failing hearts. Because the ß1AR protein is essential for cardiac output. we believe that elevated levels of AUF1 in the failing heart is detrimental to cardiac function. We are currently developing a transgenic model of cardiac AUF1 overexpression to further address this relationship. (4) We are examining how MAP kinase pathways affect AUF1 activity to stabilize interleukin-1ß and tumor necrosis factor-alpha mRNAs in monocytes that become adherent at sites of inflammation and tissue injury. (5) Finally. we are utilizing physical methods. such as measuring changes in fluorescence anisotropy. to dissect the molecular details of the binding of AUF1 to its cognate RNA sequences. Selected PublicationsBrewer G. (2007) Part A - microRNAs: discovery, analyses, targets. Methods. 43(2):89-90. Liao B, Hu Y, Brewer G. (2007) Competitive binding of AUF1 and TIAR to MYC mRNA controls its translation. Nat Struct Mol Biol. 14(6):511-8. Banihashemi L, Wilson GM, Das N, Brewer G. (2006) Upf1/Upf2 regulation of 3' untranslated region splice variants of AUF1 links nonsense-mediated and A+U-rich element-mediated mRNA decay. Mol Cell Biol. 26(23):8743-54. Lal A. Abdelmohsen K. Pullmann R. Kawai T. Galban S. Yang X. Brewer G. Gorospe M. (2006) Posttranscriptional derepression of GADD45alpha by genotoxic stress. Mol Cell. 22(1):117-28. Gupta M. Brewer G. (2006) MicroRNAs: new players in an old game. Proc Natl Acad Sci U S A. 103(11):3951-2.
Sommer S. Cui Y. Brewer G. Fuqua SA. (2005) The c-Yes 3'-UTR contains
adenine/uridine-rich elements that bind AUF1 and HuR involved in mRNA
decay in breast cancer cells. Liao. B.. Hu. Y.. Herrick. D.J.. and Brewer. G. (2005). The RNA-binding protein IMP-3 is a translational activator of insulin-like growth factor II leader-3 mRNA during proliferation of human K562 leukemia cells. J. Biol. Chem. 280: 18517-18524. Donnini. M.. Lapucci. A.. Papucci. L.. Witort. E.. Jacquier. A.. Brewer. G.. Nicolin. A.. Capaccioli. S.. and Schiavone. N. (2004). Identification of TINO - A new evolutionarily conserved BCL-2 AU-rich element RNA-binding protein. J. Biol. Chem. 279: 20154-20166. Liao. B.. Patel. M.. Hu. Y.. Charles. S.. Herrick. D.J.. and Brewer. G. (2004). Targeted knockdown of the RNA-binding protein CRD-BP promotes cell proliferation via an IGF-II-dependent pathway in human K562 leukemia cells. J. Biol. Chem. 279: 48716-48724. Brewer. G.. Saccani. S.. Sarkar. S.. Lewis. A.. and Pestka. S. (2003). Increased interleukin-10 mRNA stability in melanoma cells is associated with decreased levels of A+U-rich element binding factor AUF1. J. Interferon Cytokine Res. 23: 553-564. Wilson. G.M.. Lu. J.. Sutphen. K.. Sun. Y.. Huynh. Y.. and Brewer. G. (2003). Regulation of ARE-directed mRNA turnover involving reversible phosphorylation of AUF1. J. Biol. Chem. 278: 33029-33038. Wilson. G.M.. Lu. J.. Sutphen. K.. Suarez. Y.. Sinha. S.. Brewer. B.. Villanueva-Feliciano. E.. Ysla. R.M.. Charles. S.. and Brewer. G. (2003). Phosphorylation of p40AUF1 regulates binding to A+U-rich mRNA-destabilizing elements and protein-induced changes in ribonucleoprotein structure. J. Biol. Chem. 278: 33039-33048. |
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