| Gary Brewer
Professor
UMDNJ-RWJMS
Biochemistry & Molecular Biology
675 Hoes Lane
Piscataway, NJ 08854-5635
(732) 235-3473
FAX - 5223
brewerga@umdnj.edu |
Post-transcriptional control of gene expression in cancer, immune responses, and congestive heart failure
Rapid 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.
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