Abca3 | GeneID:302973 | Rattus norvegicus

BC088202   XM_001054547   XM_001054596   XM_001054650   XM_001054721   XM_220219  

AAH88202   Q5M866   XP_001054547   XP_001054596   XP_001054650   XP_001054721   XP_220219  

• Rn.38406 cluster

1. [ ] Whitsett JA, et al. (2005) "Genetic disorders of surfactant homeostasis." Biol Neonate. 87(4):283-287. PMID:15985750

Adaptation to air breathing at birth requires the precise orchestration of cellular processes to initiate fluid clearance, enhance pulmonary blood flow, and to synthesize and secrete pulmonary surfactant needed to reduce surface tension at the air-liquid interface in the alveoli. Genetic programs regulating the synthesis of the surfactant proteins and lipids required for the production and function of pulmonary surfactant are highly conserved across vertebrates, and include proteins that regulate the synthesis and packaging of pulmonary surfactant proteins and lipids. Surfactant proteins B and C (SP-B and -C) are small, uniquely hydrophobic proteins that play important roles in the stability and spreading of surfactant lipids in the alveolus. Deletion or mutations in SP-B and -C cause acute and chronic lung disease in neonates and infants. SP-B and -C are synthesized and packaged with surfactant phospholipids in lamellar bodies. Normal lamellar body formation requires SP-B and a member of the ATP-binding cassette (ABC) family of ATP-dependent membrane-associated transport proteins, ABCA3. Mutations in ABCA3 cause fatal respiratory disease in newborns and severe chronic lung disease in infancy. Expression of SP-B, -C, and ABCA3 are coregulated during late gestation by transcriptional programs influenced by thyroid transcription factor-1 and forkhead box a2, transcription factors that regulate both differentiation of the respiratory epithelium and transcription of genes required for perinatal adaptation to air breathing.

2. [ ] Yoshida I, et al. (2004) "Expression of ABCA3, a causative gene for fatal surfactant deficiency, is up-regulated by glucocorticoids in lung alveolar type II cells." Biochem Biophys Res Commun. 323(2):547-555. PMID:15369786

We have shown previously that the ATP-binding cassette transporter ABCA3 is expressed predominantly at the limiting membrane of the lamellar bodies in lung alveolar type II cells. Very recently, an ABCA3 gene mutation was reported in human newborns with fatal surfactant deficiency. In the present study, we have shown in rat lung that expression of the ABCA3 protein is dramatically increased after embryonic day (E) 20.5 just before birth. Expression was also markedly induced even at E18.5 when dexamethasone (Dex), which is known to accelerate surfactant formation, was administered to pregnant female rats for 3 days from E15.5. Since Dex increased the ABCA3 mRNA expression level in human alveolar type II cell line A549 cells 4-fold, we cloned and characterized the promoter region of the human ABCA3 gene. Promoter activity of the 5'-flanking region of the ABCA3 gene, which contains a potential glucocorticoid-responsive element (GRE), was up-regulated about 2-fold. Up-regulation by Dex was not observed when the GRE-containing region was deleted or when a point mutation was introduced into the GRE, and electrophoretic mobility shift assay using Dex-treated A549 nuclear extracts demonstrated specific binding of the glucocorticoid receptor to the GRE. These findings demonstrate that glucocorticoid-induced up-regulation of ABCA3 expression in vivo is mediated by transcriptional activation through the GRE in the promoter, and suggest that ABCA3 plays an important role in the formation of pulmonary surfactant, probably by transporting lipids such as cholesterol.

3. [ ] Mulugeta S, et al. (2002) "Identification of LBM180, a lamellar body limiting membrane protein of alveolar type II cells, as the ABC transporter protein ABCA3." J Biol Chem. 277(25):22147-22155. PMID:11940594

Lamellar bodies are the specialized secretory organelles of alveolar type II (ATII) epithelial cells through which the cell packages pulmonary surfactant and regulates its secretion. Surfactant within lamellar bodies is densely packed as circular arrays of lipid membranes and appears to be the product of several trafficking and biosynthetic processes. To elucidate these processes, we reported previously on the generation of a monoclonal antibody (3C9) that recognizes a unique protein of the lamellar body membrane of 180 kDa, which we named LBM180. We report that mass spectrometry of the protein precipitated by this antibody generated a partial sequence that is identical to the ATP-binding cassette protein, ABCA3. Homology analysis of partial sequences suggests that this protein is highly conserved among species. The ABCA3 gene transcript was found in cell lines of human lung origin, in ATII cells of human, rat, and mouse, as well as different tissues of rat, but the highest expression of ABCA3 was observed in ATII cells. Expression of this transcript was at its maximum prior to birth, and hormonal induction of ABCA3 transcript was observed in human fetal lung at the same time as other surfactant protein transcripts were induced, suggesting that ABCA3 is developmentally regulated. Molecular and biochemical studies show that ABCA3 is targeted to vesicle membranes and is found in the limiting membrane of lamellar bodies. Because ABCA3 is a member of a subfamily of ABC transporters that are predominantly known to be involved in the regulation of lipid transport and membrane trafficking, we speculate that this protein may play a key role in lipid organization during the formation of lamellar bodies.

4. [ ] Strausberg RL, et al. (2002) "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences." Proc Natl Acad Sci U S A. 99(26):16899-16903. PMID:12477932

The National Institutes of Health Mammalian Gene Collection (MGC) Program is a multiinstitutional effort to identify and sequence a cDNA clone containing a complete ORF for each human and mouse gene. ESTs were generated from libraries enriched for full-length cDNAs and analyzed to identify candidate full-ORF clones, which then were sequenced to high accuracy. The MGC has currently sequenced and verified the full ORF for a nonredundant set of >9,000 human and >6,000 mouse genes. Candidate full-ORF clones for an additional 7,800 human and 3,500 mouse genes also have been identified. All MGC sequences and clones are available without restriction through public databases and clone distribution networks (see http:mgc.nci.nih.gov).