Apobec-1 protects intestine from radiation injury through posttranscriptional regulation of cyclooxygenase-2 expression

Anant, Shrikant; Murmu, Nabendu; Houchen, Courtney W.; Mukhopadhyay, Debnath; Riehl, Terrence E.; Young, Stephen G.; Morrison, Adam; Stenson, William F.; Davidson, Nicholas O.

doi:10.1053/j.gastro.2004.06.022

Cited by 44 publications

(49 citation statements)

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“…In addition, we must consider that, through RNA targeting, APOBEC1 can alter a number of cellular functions [11,13,14,27]. It is possible, therefore, that these changes, associated with APOBEC1 mutagenic activity, may also be boosting its oncogenic potential and drive both the onset and the progression of cancer.…”

Section: Discussionmentioning

confidence: 99%

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The RNA editing enzyme APOBEC1 induces somatic mutations and a compatible mutational signature is present in esophageal adenocarcinomas

et al. 2014

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Background: The AID/APOBECs are deaminases that act on cytosines in a diverse set of pathways and some of them have been linked to the onset of genetic alterations in cancer. Among them, APOBEC1 is the only family member to physiologically target RNA, as the catalytic subunit in the Apolipoprotein B mRNA editing complex. APOBEC1 has been linked to cancer development in mice but its oncogenic mechanisms are not yet well understood. Results: We analyze whether expression of APOBEC1 induces a mutator phenotype in vertebrate cells, likely through direct targeting of genomic DNA. We show its ability to increase the inactivation of a stably inserted reporter gene in a chicken cell line that lacks any other AID/APOBEC proteins, and to increase the number of imatinib-resistant clones in a human cellular model for chronic myeloid leukemia through induction of mutations in the BCR-ABL1 fusion gene. Moreover, we find the presence of an AID/APOBEC mutational signature in esophageal adenocarcinomas, a type of tumor where APOBEC1 is expressed, that mimics the one preferred by APOBEC1 in vitro.

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Section: Discussionmentioning

confidence: 99%

“…The only well-characterized target for APOBEC1 is the mRNA for Apolipoprotein B; however, additional target mRNAs have been identified [10][11][12], and it has been also suggested that APOBEC1 regulates mRNA stability through its ability to bind RNA [13,14]. On the other hand, APOBEC1 can also target DNA in bacteria and in vitro [15][16][17].…”

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confidence: 99%

The RNA editing enzyme APOBEC1 induces somatic mutations and a compatible mutational signature is present in esophageal adenocarcinomas

et al. 2014

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“…The full-length 3Ј-UTR was cloned behind a green fluorescent protein cDNA as a reporter for mRNA stability studies using actinomycin D (5 g/ml), as detailed previously (33). Three individual fragments, collectively spanning the entire Cyp7a1 3Ј-UTR, were used for RNA binding studies.…”

Section: Animals and Diets-apobec-1mentioning

confidence: 99%

“…These results suggested the possibility that APOBEC-1 modulates posttranscriptional regulation of Cyp7a1 gene expression. Accordingly, we examined the possibility that APOBEC-1, an RNA-binding protein with affinity for AU-rich targets beyond ApoB mRNA (33,36), might exhibit RNA binding activity toward the Cyp7a1 3Ј-UTR, a region of the transcript that contains a large number of AU-rich motifs and the UUUN(A/U)U consensus site for APOBEC-1 binding (36) (Fig. 7B).…”

Section: Post-transcriptional Modulation Of Cyp7a1 Gene Expression Inmentioning

confidence: 99%

“…The finding that RNA transcription rates were comparable in wild type and Apobec-1 Ϫ/Ϫ mice most plausibly suggests that the decreased Cyp7a1 expression in Apobec-1 Ϫ/Ϫ mice reflects a post-transcriptional mechanism. We have previously demonstrated that APO-BEC-1 binds AU-rich RNA templates, particularly those containing the high affinity consensus sequence (UUUN(A/U)U) embedded within its canonical target ApoB RNA as well as others, including c-Myc and Cox-2, and demonstrated that APO-BEC-1 binding to these RNA templates also modulates mRNA stability (33,36). Other work has established a strong precedent for posttranscriptional regulation of Cyp7a1 mRNA, and several authors have pointed out the short half-life (ϳ30 min to 1 h) of Cyp7a1 mRNA both in cell culture (42) and in vivo in rat (43)(44)(45) and hamster liver (46).…”

Section: Apobmentioning

confidence: 99%

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Decreased Expression of Cholesterol 7α-Hydroxylase and Altered Bile Acid Metabolism in Apobec-1−/− Mice Lead to Increased Gallstone Susceptibility

Blanc

Kerr

Kennedy

et al. 2009

Journal of Biological Chemistry

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Quantitative trait mapping in mice identified a susceptibility locus for gallstones (Lith6) spanning the Apobec-1 locus, the structural gene encoding the RNA-specific cytidine deaminase responsible for production of apolipoprotein B48 in mammalian small intestine and rodent liver. This observation prompted us to compare dietary gallstone susceptibility in Apobec-1 mice, excluding transcriptional repression as a potential mechanism for decreased Cyp7a1 expression. We demonstrated that APOBEC-1 binds to AU-rich regions of the 3-untranslated region of the Cyp7a1 transcript, containing the UUUN(A/U)U consensus motif, using both UV cross-linking to recombinant APOBEC-1 and in vivo RNA co-immunoprecipitation. In vivo Apobec-1-dependent modulation of Cyp7a1 expression was further confirmed following adenovirus-Apobec-1 administration to chow-fed Apobec-1 ؊/؊ mice, which rescued Cyp7a1 gene expression. Taken together, the findings suggest that the AUrich RNA binding-protein Apobec-1 mediates post-transcriptional regulation of murine Cyp7a1 expression and influences susceptibility to diet-induced gallstone formation.Cholesterol gallstone disease is highly prevalent among western societies and represents a substantial and recurrent financial burden to the health care economy (1). Considerable attention has focused on the observations that gallbladder disease and cholelithiasis demonstrate familial clustering and that shared genetic factors account for a significant portion of the risk, although environmental modifiers as well as age, gender, body habitus, and ethnicity are also of major importance (reviewed in Ref. 2). However, despite intensive study over many decades, questions remain regarding the mechanisms by which biliary cholesterol becomes supersaturated, leading to the formation of cholesterol monohydrate crystals that eventually nucleate and result in gallstone formation (reviewed in Ref. 3).Insight into the genetic factors that underlie cholesterol gallstone disease has emerged from the study of inbred mouse strains where intercrosses between gallstone-susceptible and -resistant strains have generated a comprehensive array of candidate loci through quantitative trait locus mapping, an approach that has yielded at least 23 LITH loci (2, 4). Among the quantitative trait loci identified through this approach is Lith6, a locus on mouse chromosome 6 that mapped to a region that includes Apobec-1 as well as other genes (Pparg and Slco1a1) involved in lipid metabolism (5). Apobec-1, the RNA-specific catalytic deaminase of the mammalian ApoB (apolipoprotein B) mRNA-editing enzyme (6), mediates C to U RNA editing of intestinal ApoB RNA, leading to production of APOB48, the major structural protein on chylomicrons (7). In addition, mouse and rat (but not human) liver exhibit physiologically regulated Apobec-1-dependent ApoB mRNA editing accompanying a range of developmental, nutritional, and hormonal cues, resulting in the ability of murine hepatocytes to synthesize APOB100 and APOB48 in varying proportions with accompan...

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Therapeutic Rna Manipulation in Liver Disease

Kerr

Davidson

2010

Hepatology

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Posttranscriptional regulation of gene expression is increasingly recognized as a model for inherited and acquired disease. Recent work has expanded understanding of the range of mechanisms that regulate several of these distinct steps, including messenger RNA (mRNA) splicing, trafficking, and/or stability. Each of these pathways is implicated in disease pathogenesis, and each represents important avenues for therapeutic intervention. This review summarizes important mechanisms controlling mRNA processing and the regulation of mRNA degradation, including the role of microRNAs and RNA binding proteins. These pathways provide important opportunities for therapeutic targeting directed at splicing and degradation in order to attenuate genetic defects in RNA metabolism. We will highlight developments in vector development and validation for therapeutic manipulation of mRNA expression with a focus on potential applications in metabolic and immunomediated liver disease.(HEPATOLOGY 2010;51:1055-1061.) RNA Synthesis, Processing, and Posttranscriptional RegulationMessenger RNA (mRNA) synthesis is accompanied by cotranscriptional addition of two major stability elements. These include 7-methyl guanosine (m 7 G) capping at the 5Ј end of the mRNA transcript, which prevents 5Ј exonuclease digestion and addition of a variable length poly-A tail to the 3Ј end of the mRNA. Splicing of introncontaining transcripts occurs in the nucleus and is mediated by spliceosomal apparati composed of distinctive small nuclear ribonucleoprotein complexes 1 and amplifies the number of translation products generated from a single genomically templated transcript. Enhancers and repressors of splicing exert additional combinatorial control over other posttranscriptional modifications including RNA editing. 1,2 Following or simultaneous with 5Ј and 3Ј end modifications and splicing of the nuclear transcript, mRNAs are bound to a complex of nuclear export factors to form a ribonucleoprotein complex. The ribonucleoprotein complex interacts with the nuclear pore complex for translocation to the cytoplasm. 3 The m 7 G cap is bound by elongation initiation factor 4E and other cytoplasmic eIF4 proteins, which then engage by way of eIF3 directly to ribosomes to facilitate mRNA translational initiation. 4 Similarly, poly-A binding protein also accelerates mRNA translation through activation of the helicase activity of the eIF4 complex. 5 Mechanisms and Pathways for RNA DegradationEukaryotic mRNA half-lives range from minutes to months, the predominant mechanism limiting mRNA longevity being transcript deadenylation. mRNA transcripts earmarked for destruction undergo initial removal of the 5Ј m 7 G cap by decapping enzymes 6 or alternatively the 3Ј poly-A tail may be targeted by deadenylases. 7 Poly-A tails are deadenylated at differing rates, mRNAs containing long poly-A tails (Ͼ55 adenosines) being generally more efficiently translated. 8 During cellular stress (such as glucose deprivation), 9,10 or when the mRNA decay machinery is overloaded, mRNA transc...

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Apobec-1 protects intestine from radiation injury through posttranscriptional regulation of cyclooxygenase-2 expression

Cited by 44 publications

References 47 publications

The RNA editing enzyme APOBEC1 induces somatic mutations and a compatible mutational signature is present in esophageal adenocarcinomas

The RNA editing enzyme APOBEC1 induces somatic mutations and a compatible mutational signature is present in esophageal adenocarcinomas

Decreased Expression of Cholesterol 7α-Hydroxylase and Altered Bile Acid Metabolism in Apobec-1−/− Mice Lead to Increased Gallstone Susceptibility

Therapeutic Rna Manipulation in Liver Disease

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