Fibroblasts from long-lived Snell dwarf mice are resistant to oxygen-induced in vitro growth arrest.
Snell dwarf mice live longer than controls, and show lower age-adjusted rates of lethal neoplastic diseases. Fibroblast cells from adult dwarf mice are resistant to the lethal effects of oxidative and nonoxidative stresses, including the carcinogen methyl methanesulfonate. We now report that dwarf-derived fibroblasts are slow to enter the stage of growth arrest induced by culturing normal cells under standard culture conditions at 20% O(2). Dwarf cells cultured at 20% O(2) resemble control cells cultured at 3% O(2) not only in their delayed growth arrest, but also in their rapid growth rates and resistance to both oxidative and nonoxidative forms of cytotoxic stress. Levels of the heat-shock protein HSP-70 respond to serum withdrawal and stress only in control cells, showing that intracellular signals are blunted in dwarf-derived cells. These data suggest a model in which stable epigenetic changes induced in skin fibroblasts by the hormonal milieu of the Snell dwarf lead to resistance to multiple forms of injury, including the oxidative damage that contributes to growth arrest in vitro and neoplasia in intact mice.
Maynard
Scott P
SP
Department of Pathology and Geriatrics Center, University of Michigan, and Ann Arbor VA Medical Center, Ann Arbor, MI 48109-0940, USA.
Miller
Richard A
RA
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000494:pharmacology*
D016895:Culture Media, Serum-Free; D018840:HSP70 Heat-Shock Proteins; D010100:Oxygen