Nicholas O. Davidson, M.D.

Professor
Internal Medicine
Gastroenterology
Division Chief
Developmental Biology

Molecular Cell Biology Program
Biochemistry, Biophysics, and Structural Biology Program

  • 314-362-2027

  • 314-747-2909

  • 314-362-2033

  • 8124

  • 910 Clinical Sciences Research Building, North Tower

  • nod@wustl.edu

  • http://gastro.wustl.edu/faculty/davidson.html

  • gene expression, RNA, cancer, mRNA editing, mRNA stability

  • Mammalian gene expression: Regulation through mRNA editing and RNA stabilization

Research Abstract:

Our lab studies the mechanisms and consequences of alterations in gene regulation, principally through changes in mRNA stability and posttranscriptional editing. We study the model of C to U RNA editing, which changes a CAA-> UAA translational stop (UAA) in intestinal apoB mRNA, and results in translational termination of apoB48. ApoB mRNA editing has important metabolic consequences for lipid metabolism and our group is interested in the genetic regulation of intestinal and hepatic lipid metabolism since these pathways have major effects on obesity and hepatic steatosis. Our laboratory cloned the catalytic subunit of the apoB RNA editing enzyme, an RNA-specific cytidine deaminase, Apobec1. We are interested in how Apobec1 finds its target (1 nucleotide in over 14,000) with such precision. One explanation is that Apobec1 binds to a partner protein (Apobec1 complementation factor, ACF) which is itself an RNA-binding protein and our work suggests that it is ACF-RNA binding that determines the specificity of Apobec1 C to U deamination. However, Apobec1 is also an RNA binding protein, with specificity for A+U rich templates. We have determined that other RNA targets exist for both Apobec1 binding and for ACF and we believe that the biological functions of both these genes reflects their interactions with this array of possible targets. We have mapped a high-affinity binding site for Apobec1, which, interestingly, is present in c-myc, COX-2, TNF-alpha and IL-2 mRNAs. Moreover, Apobec1 binding alters mRNA stability of these targets in both cell lines and animal tissues. Since we are interested in the implications of our work for human disease, we were intrigued by the finding that Apobec1-/- mice demonstrate reduced COX-2 mRNA stability in vivo. This is of interest since COX-2 mRNA and protein increase in human subjects with adenomatous colonic polyps and COX-2 mRNA increases further in colon cancer. This suggests that strategies to reduce COX-2 expression might abrogate the development of colon cancer. Genetic crosses of Apobec1 -/- mice into a strain of mice that develops intestinal polyps have now demonstrated protection from intestinal polyposis and reduced COX-2 expression, suggesting that Apobec1 may conceivably be a modifier of colon cancer susceptibility in humans. In addition, we are studying the function of the AU-rich RNA binding protein and Apobec1 partner, ACF. Mouse knockouts are early embryonic lethal, suggesting that ACF is required in a non-redundant manner for blastocyst implantation. Similarly, ACF knockdown in somatic cells leads to apoptosis and cell death. We are actively pursuing the range of RNA targets to which ACF binds, in-vivo.

Selected Publications:

Xie, Y, Luo, J, Kennedy, S, Davidson, NO. Conditional intestinal lipotoxicity in Apobec-1-/- Mttp-IKO mice: A survival advantage for mammalian intestinal apolipoprotein B mRNA editing. J. Biol. Chem. 2007 282:33043-33051.

Blanc, V, Henderson, JO, Cho, SJ, et al. Deletion of the AU-rich RNA binding protein apobec-1 reduces intestinal tumor burden in Apcmin mice. Cancer Research 2007 67:8565-8573.

Blanc V, Henderson JO, Newberry EP, et al. Targeted deletion of the murine apobec-1 complementation factor (acf) gene results in embryonic lethality. Mol Cell Biol 2005 26(16):7260-7269.

Anant S, Murmu N, Houchen CW, et al. Apobec-l protects intestine from radiation injury through posttranscriptional regulation of cyclooxygenase-2 expression. Gastroenterology 2004 127:1139-1149.

Anant S, Davidson NO. An AU-rich sequence element [UUUN(A/U)U] downstream of the edited C in apolipoprotein B mRNA is a high affinity binding site for apobec-1: Binding of this motif in the 3’ untranslated region of c-myc increases mRNA stability. Mol Cell Biol 2000 20:1982-1992.

Last Updated: 8/3/2011 3:04:40 PM

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