Jeffrey O. Henderson

University of Washington Seattle, Seattle, WA, United States

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Publications (9)76.45 Total impact

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    ABSTRACT: The RNA-specific cytidine deaminase apobec-1 is an AU-rich RNA binding protein that binds the 3' untranslated region (UTR) of cyclooxygenase-2 (Cox-2) mRNA and stabilizes its turnover in vitro. Cox-2 overexpression accompanies intestinal adenoma formation in both humans and mice. Evidence from both genetic deletion studies as well as from pharmacologic inhibition has implicated Cox-2 in the development of intestinal adenomas in experimental animals and in adenomas and colorectal cancer in humans. Here, we show that small intestinal adenoma formation is dramatically reduced in compound Apc(min/+) apobec-1(-/-) mice when compared with the parental Apc(min/+) strain. This reduced tumor burden was found in association with increased small intestinal apoptosis and reduced proliferation in small intestinal crypt-villus units from compound Apc(min/+) apobec-1(-/-) mice. Intestinal adenomas from compound Apc(min/+) apobec-1(-/-) mice showed a <2-fold increase in Cox-2 mRNA abundance and reduced prostaglandin E(2) content compared with adenomas from the parental Apc(min/+) strain. In addition, there was reduced expression in adenomas from compound Apc(min/+) apobec-1(-/-) mice of other mRNAs (including epidermal growth factor receptor, peroxisome proliferator-activated receptor delta, prostaglandin receptor EP4, and c-myc), each containing the apobec-1 consensus binding site within their 3'-UTR. Adenovirus-mediated apobec-1 introduction into HCA-7 (colorectal cancer) cells showed a dose-dependent increase in Cox-2 protein and stabilization of endogenous Cox-2 mRNA. These findings suggest that deletion of apobec-1, by modulating expression of AU-rich RNA targets, provides an important mechanism for attenuating a dominant genetic restriction point in intestinal adenoma formation.
    Cancer Research 09/2007; 67(18):8565-73. · 9.28 Impact Factor
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    ABSTRACT: Expression of anti-apoptotic genes is frequently elevated in tumors, where they increase resistance to chemotherapeutic agents and predict poor patient outcomes. However, key cellular factors regulating anti-apoptotic genes in tumors remain unknown. Increased expression of the regenerating (Reg) genes is commonly observed in gastrointestinal (GI) malignancies including colorectal cancer (CRC). We therefore examined Reg gene expression and associated changes in anti-apoptotic genes in an animal model of GI tumorigenesis. Using real time RT-PCR, we measured expression of Reg genes in human colorectal adenocarcinoma specimens, colon adenocarcinoma cell lines and adenomas from multiple intestinal neoplasia (min) mice heterozygous for a germ-line mutation of the adenomatous polyposis coli (APC) gene. Expression of Reg genes is increased in human colorectal adenocarcinomas and in the intestine of APCmin/+ mice at four weeks of age, a time preceding the spontaneous second mutation in the APC gene. Individual Reg genes exhibited regional expression profiles across the GI tract in mice. Adenomas from 14-week old mice had significant increases in at least one member of the Reg gene family, most commonly Reg IV and an associated increase in expression of the anti-apoptotic gene, Bcl-2. Addition of exogenous recombinant human Reg IV to human colon adenocarcinoma cells significantly increased Bcl-2 and Bcl-xL expression and induced resistance to ionizing radiation. These results show that dysregulation of Reg genes occur early in tumorigenesis. Furthermore, increased expression of Reg genes, specifically Reg IV contribute to adenoma formation and lead to increased resistance to apoptotic cell death in CRC.
    Cancer biology & therapy 01/2007; 5(12):1714-20. · 3.63 Impact Factor
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    ABSTRACT: apobec-1 complementation factor (ACF) is an hnRNP family member which functions as the obligate RNA binding subunit of the core enzyme mediating C-to-U editing of the nuclear apolipoprotein B (apoB) transcript. ACF binds to both apoB RNA and apobec-1, the catalytic cytidine deaminase, which then results in site-specific posttranscriptional editing of apoB mRNA. Targeted deletion of apobec1 eliminates C-to-U editing of apoB mRNA but is otherwise well tolerated. However, the functions and potential targets of ACF beyond apoB mRNA editing are unknown. Here we report the results of generating acf knockout mice using homologous recombination. While heterozygous acf(+/)(-) mice were apparently healthy and fertile, no viable acf(-)(/)(-) mice were identified. Mutant acf(-)(/)(-) embryos were detectable only until the blastocyst (embryonic day 3.5 [E3.5]) stage. No acf(-)(/)(-) blastocysts were detectable following implantation at E4.5, and isolated acf(-)(/)(-) blastocysts failed to proliferate in vitro. Small interfering RNA knockdown of ACF in either rat (apobec-1-expressing) or human (apobec-1-deficient) hepatoma cells decreased ACF protein expression and induced a commensurate increase in apoptosis. Taken together, these data suggest that ACF plays a crucial role, which is independent of apobec-1 expression, in cell survival, particularly during early embryonic development.
    Molecular and Cellular Biology 09/2005; 25(16):7260-9. · 5.04 Impact Factor
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    ABSTRACT: There is a significant need for noninvasive methods of evaluating dysplastic and neoplastic lesions in the luminal gastrointestinal tract. We have optimized an approach based on autofluorescence to study dysplastic adenomatous polyps in Apc(min/+) mice. We made recordings from both normal intestinal mucosa and from polyps using a xenon lamp-based fiberoptic device. Seventy-eight polyps in 11 mice revealed an increase in mean autofluorescence intensity ratios of 1.29 +/- 0.04 (72 small intestinal polyps; P < 0.0001) and 1.28 +/- 0.05 (6 colon polyps; P = 0.0016). Serial measurements of autofluorescence discriminated polyps from normal mucosa with a sensitivity, verified histologically, of 95%. To understand the chemical basis for increased autofluorescence, we examined the tryptophan content of intestinal polyps and the adjacent normal mucosa in a small subset of animals. The findings revealed an increased concentration of tryptophan in polyps (990 +/- 240 ng/mg) compared to normal mucosa (720 +/- 150 ng/mg; P = 0.03). In conclusion, these findings suggest that autofluorescence intensity increases in the setting of intestinal neoplasia and can be used to detect adenomas in the mouse intestine in real time.
    Digestive Diseases and Sciences 01/2004; 49(1):54-9. · 2.55 Impact Factor
  • Gastroenterology 04/2003; 124(4). · 12.82 Impact Factor
  • Gastroenterology 04/2003; 124(4). · 12.82 Impact Factor
  • Bhaskar Banerjee, Nicholas O. Davidson, Jeffrey O. Henderson
    Gastroenterology 04/2003; 124(4). · 12.82 Impact Factor
  • Jeffrey O. Henderson, Valerie Blanc, Nicholas O. Davidson
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    ABSTRACT: Mammalian apolipoprotein B (apo B) mRNA undergoes site-specific C to U deamination which is mediated by a multicomponent enzyme complex containing a minimal core composed of apobec-1 and a complementation factor, ACF. We have isolated and characterized the human ACF gene and examined its tissue-specific and developmental expression. The ACF gene spans ∼80 kb and contains 15 exons, three of which are non-coding. Multiple alternative splice acceptor sites were found, generating at least nine different transcripts. Of these, the majority (∼75–89%) encode functional protein. In order to examine the role of ACF mRNA expression in the regulation of apo B mRNA editing, we examined a panel of fetal intestinal and hepatic mRNAs as well as RNA from an intestinal cell line. A developmental increase in C to U RNA editing has been previously noted in the human intestine. In both instances, the pattern of alternative splicing and overall abundance of ACF mRNA was relatively constant during development in both liver and small intestine. Taken together, the data demonstrate a complex pattern of differential, tissue-specific splicing of ACF mRNA, but suggest that other mechanisms are responsible for the developmental increase noted in intestinal apo B mRNA editing in humans.
    Biochimica et Biophysica Acta 12/2001; · 4.66 Impact Factor
  • Gastroenterology 04/2000; 118(4). · 12.82 Impact Factor

Publication Stats

80 Citations
76.45 Total Impact Points

Institutions

  • 2001–2007
    • University of Washington Seattle
      • • Department of Medicine
      • • Division of Gastroenterology
      • • Division of General Internal Medicine
      Seattle, WA, United States
  • 2004
    • Washington University in St. Louis
      • Division of Gastroenterology
      Saint Louis, MO, United States