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MORPHOLOGIC ANALYSIS CORRELATES WITH GENE EXPRESSION CHANGES IN CULTURED F344 RAT MESOTHELIAL CELLS
Citation:
Crosby, L. M., K. S. Hyder, A B. DeAngelo, T. A. Kepler, B. Gaskill, G. R. Benavides, L. Yoon, AND K. T. Morgan. MORPHOLOGIC ANALYSIS CORRELATES WITH GENE EXPRESSION CHANGES IN CULTURED F344 RAT MESOTHELIAL CELLS. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press, New York, NY, 169(3):205-221, (2001).
Description:
The gene expression pattern of mesothelial cells in vitro was determined after 4 or 12 h exposure to the rat mesothelial, kidney and thyroid carcinogen, and oxidative stressor potassium bromate (KBr03). Gene expression changes observed using cDNA arrays indicated oxidative stress, mitotic arrest and apoptosis in treated immortalized rat peritoneal mesothelial cells. Increases occurred in oxidative stress responsive genes H0-11, QR2, HSP703, GADD454, GADD1535, p21 WAF1/C1P16, GST's7, GAPDH8, TPX9 AND GPX-110; transcriptional regulators c-jun, c-fos, jun D, jun B, c-myc and 1 B11; protein repair components R , RC10-II, C3, RC-7, HR6B ubiquitin-cojungating enzyme and ubiquitin; DNA repair components PCNA12, msh213 and 0-6 methylguaanine DNA methyltransferase; lipid peroxide excision enzyme PLA214 and apoptogenic components TNF 15, iNOS116 and FasL17, Decreases occurred in bcl-218 (anti-apoptotic), bax 19, bad20 and bok21 (pro-apoptotic) and cell cycle control elements (cyclins). Cyclin G, p14ink4b22 (which inhibit entry into cell cycle) were increased. Numerous signal transduction, cell membrane transport, membrane-associated receptor and fatty acid biosynthesis and repair components were altered. Morphologic endpoints examined were; number of mitotic figures, number of apoptotic cells, and antibody-specific localization of H0?1. PCR analysis confirmed H0-1, p21waf1/cip1, HSP70, GPX1, GADD45, QR, mdr123, PGHS24 and cyclin D1 changes. A model for KBr03-induced carcinogenicity in the F344 rat mesothelium is proposed, whereby KBr03 generates a redox signal that activates p53 and results in transcriptional activation of oxidative stress and repair genes, dysregulation of growth control, and imperfect DNA repair leading to carcinogenesis.