title: Cyclin A expression in normal and transformed alveolar epithelial cells.
abstract: The mature adult alveolar epithelial cell (AEC) is a highly differentiated phenotype that does not readily divide and exhibits numerous specialized functions. Yet, transformed AEC proliferate aggressively in certain forms of lung cancer. Normal AEC also proliferate but in a coordinated manner during embryonic growth and fetal development as well as during lung repair. Therefore, biochemical mechanisms regulating the cell cycle in AEC are clearly of fundamental significance for understanding lung development, lung injury, and cancer. Cyclin A is a protein that varies in abundance during the cell cycle and regulates critical transition points through its association with cyclin-dependent protein kinase subunits. We postulated that high expression of cyclin A might be associated with rapid proliferation in transformed AEC. We compared the expression of cyclin A mRNA and protein in primary cultures of fetal and adult rat AEC, in the E1A-T2 neonatal rat AEC, and in the malignant A549 human AEC. We used pharmacologic blockades with mimosine, aphidicolin, and nocodazole for cell cycle synchronization, which was verified by fluorescence-activated cell sorter (FACS) analysis of cellular DNA content. Transformed cells (A549 and E1A-T2) exhibited a much higher level of expression for both cyclin A mRNA and protein than did normal rat AEC. Induction of cyclin A mRNA expression in A549 human AEC and E1A-T2 rat AEC occurred in late G1, prior to the onset of S phase. Fetal and adult rat AEC and rat E1A-T2 AEC expressed two cyclin A mRNA transcripts, whereas human A549 cells in S phase and M phase expressed three cyclin A mRNA transcripts. We conclude that transformed AEC overexpress cyclin A in comparison with primary AEC cultures, while retaining cell cycle-dependent differences in cyclin A expression. We speculate that cyclin A expression is regulated both at the transcriptional and post-transcriptional levels, and that cyclin A may play a key role in the increased proliferation of transformed AEC that is associated with the pathogenesis of lung cancer.
authors.affiliation: Division of Neonatology and Pediatric Pulmonology, Childrens Hospital Los Angeles, University of Southern California School of Medicine 90027.
authors.forename: K C
authors.initials: KC
authors.lastname: Bui
authors.forename: F
authors.initials: F
authors.lastname: Wu
authors.forename: S
authors.initials: S
authors.lastname: Buckley
authors.forename: L
authors.initials: L
authors.lastname: Wu
authors.forename: R
authors.initials: R
authors.lastname: Williams
authors.forename: D
authors.initials: D
authors.lastname: Carbonaro-Hall
authors.forename: F L
authors.initials: FL
authors.lastname: Hall
authors.forename: D
authors.initials: D
authors.lastname: Warburton
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics; D002461:Cell Line, Transformed; D002469:Cell Separation; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004848:Epithelium / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008898:Mimosine / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014407:Tumor Cells, Cultured
chemical_list: D016213:Cyclins; D012333:RNA, Messenger; D008898:Mimosine; D004247:DNA