Disease relevance of Apobec1

• In contrast, in apoE-/- mice, inactivation of apobec-1 caused a massive increase (from <0.5 to 55.5+/-16.4 mg/dL) in plasma apoB-100 concentration but an approximately 55% reduction in hypercholesterolemia due to partial amelioration of the marked VLDL+IDL elevation [1].
• Apobec-1 protects intestine from radiation injury through posttranscriptional regulation of cyclooxygenase-2 expression [2].
• A recent report showing induction of DNA mutations in Escherichia coli by overexpression of AID, Apobec-1, and related members of the RNA-editing cytidine deaminase family suggested that they may directly modify deoxycytidine in DNA in mammalian cells (DNA-editing model) [3].
• However, when the catalytic subunit of the editing enzyme complex, APOBEC-1, was overexpressed in transgenic mice and rabbits, numerous cytidines in the apoB mRNA and in a novel mRNA, NAT1, were aberrantly hyperedited, and the animals developed liver dysplasia and hepatocellular carcinomas [4].
• Promoter-luciferase reporter constructions using regions flanking exon A and exon 1 of the rat apobec-1 gene identified two functional regions upstream of exon 1 that independently promote luciferase expression in transfected hepatoma and colon cancer cells [5].
• 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 [6].

High impact information on Apobec1

• Moreover, the physiological role of the apolipoprotein B RNA editing enzyme APOBEC-1 has been investigated in genetically manipulated mice [7].
• Transgene expression of the apolipoprotein B mRNA-editing enzyme (APOBEC-1) causes dysplasia and carcinoma in mouse and rabbit livers [8].
• Alternatively, AID functions like its closest homologue Apobec1 as a catalytic subunit of a RNA editing holoenzyme ('RNA-substrate model') [9].
• Upon binding to the AU-rich sequences, apobec-1 stabilizes cyclooxygenase-2 messenger RNA [2].
• RESULTS: After gamma-irradiation, the survival of intestinal stem cells decreased significantly in APOBEC-1(-/-) mice [2].

Biological context of Apobec1

• Hepatic gene expression profiling reveals perturbed calcium signaling in a mouse model lacking both LDL receptor and Apobec1 genes [10].
• Apobec-1 is the catalytic subunit of a multicomponent editosome complex that mediates apolipoprotein B (apoB) mRNA editing [11].
• We conclude that apobec-1(-/-) animals have a distinctive lipoprotein phenotype characterized by significant hyperapoB-100 and HDL deficiency in mice with a wild-type genetic background [12].
• We have used gene targeting to disrupt mouse apobec-1 in order to establish its requisite importance in apoB mRNA editing and also, in view of its widespread tissue distribution in rodents, as a preliminary indication of other potential roles [13].
• BACKGROUND & AIMS: This study aimed to determine the role of the RNA binding protein apobec-1 in radioprotection of the intestine [2].

Anatomical context of Apobec1

• To directly test this, mice were created with a null mutation in Apobec-1 using homologous recombination in embryonic stem cells [14].
• By contrast, levels of small intestinal apoB mRNA editing were indistinguishable in wild-type and apobec-1+/- animals, suggesting that Apobec-1 is expressed in limited quantities in the liver but not in the small intestine [13].
• We therefore examined whether Apobec-1 bona fide RNA-editing enzyme could show somatic hypermutation and class switching activities in murine B lymphocytes and fibroblasts [3].
• To determine whether APOBEC-1 can therefore substitute for AID in activated B cells, we expressed human AID, a catalytic mutant thereof, and rat APOBEC-1 in AID-deficient murine B cells [15].
• These data serve as a basis for an understanding of the regulation of apobec-1 gene expression, in particular the mechanisms that serve to restrict its expression to the gastrointestinal tract in higher mammals [5].

Associations of Apobec1 with chemical compounds

• Effective lowering of plasma, LDL, and esterified cholesterol in LDL receptor-knockout mice by adenovirus-mediated gene delivery of ApoB mRNA editing enzyme (Apobec1) [16].
• Both heterozygous (apobec-1+/-) and homozygous (apobec-1-/-) gene-targeted mice appear healthy and fertile with no alterations in serum cholesterol or triglyceride concentrations [13].
• METHODS: Apobec-1-deleted mice (APOBEC-1(-/-)) and wild-type controls were treated with 12 Gy of whole-body gamma-irradiation in a cesium irradiator [2].
• CONCLUSIONS: Lipopolysaccharide increases intestinal stem cell survival through apobec-1-mediated regulation of cyclooxygenase-2 messenger RNA stability [2].
• The editing enzyme, called apobec-1, converts a cytidine (C) at nucleotide 6666 in apoB 100 mRNA to a uridine (U) and changes a CAA codon to an in-frame stop codon, UAA [17].

Regulatory relationships of Apobec1

• Hepatic secretion of small lipoprotein particles in apobec-1-/- mice is regulated by the LDL receptor [18].

Other interactions of Apobec1

• Alternative mRNA splicing and differential promoter utilization determine tissue-specific expression of the apolipoprotein B mRNA-editing protein (Apobec1) gene in mice. Structure and evolution of Apobec1 and related nucleoside/nucleotide deaminases [19].
• We conclude that in the absence of a functioning LDL receptor, hepatic overexpression of Apobec1 is highly efficient in lowering plasma apoB-100 levels, leading to the almost complete elimination of LDL particles and a reduction in LDL cholesterol and cholesteryl ester content [16].
• Hepatic apobec-1 complementation factor mRNA and protein abundance were significantly decreased, whereas apobec-1 mRNA and protein abundance remained unchanged [20].
• Hepatic ACF mRNA and protein abundance decreased in Pax8(-/-) mice, with restoration after thyroid hormone administration, whereas apobec-1 mRNA and protein abundance were unchanged [21].
• TP ligands, including COX-1 (but not COX-2)-derived TxA2, promote initiation and early progression of atherogenesis in Apobec-1/LDLR DKOs but appear unimportant in the maintenance of established disease [22].

Analytical, diagnostic and therapeutic context of Apobec1

• By fast protein liquid chromatography (FPLC) analysis, there was a significant decrease in plasma high density lipoprotein (HDL) cholesterol in apobec-1(-/-) mice [12].
• Finally, these findings compromise the potential use of APOBEC-1 for gene therapy to lower plasma levels of low density lipoproteins [23].
• We tested the editing activity and dimerization potential of three different mouse APOBEC-1 mutants using in vitro editing activity assay and immunoprecipitation in the presence of epitope-tagged APOBEC-1 [24].

References