title: Ras stimulates aberrant cell cycle progression and apoptosis in rat thyroid cells.
abstract: Abundant evidence supports the ability of Ras to stimulate thyroid cell proliferation. Stable expression of activated Ras enhances the sensitivity of thyroid cells to apoptosis. We report that apoptosis is a primary and general response of rat thyroid cells to acute expression of activated Ras in the absence or presence of thyrotropin, insulin, and serum, survival factors for thyroid cells. Ras induced apoptosis in quiescent and cycling cells. Concomitantly, Ras stimulated S phase entry in quiescent cells and enhanced G1/S transition in cycling cells. Ras effects on the cell cycle were characterized by delayed progression through S phase and an apparent failure to proceed through G2/M phase. Unlike thyroid cell mitogens, Ras markedly decreased cyclin D1 expression. Although acute expression of Ras decreased cyclin D1 protein levels, cells selected to survive chronic Ras expression exhibited a selective increase in cyclin D1 expression. In summary, thyroid cells harbor an apoptotic program activated by Ras that outstrips the protective effects of thyrotropin, insulin, and serum. Apoptosis is accompanied by dysregulated cell cycle progression, suggesting that cell death may arise, at least in part, as a consequence of inappropriate proliferative cues.
authors.affiliation: Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084, USA.
authors.forename: Guanjun
authors.initials: G
authors.lastname: Cheng
authors.forename: Aurélia E
authors.initials: AE
authors.lastname: Lewis
authors.forename: Judy L
authors.initials: JL
authors.lastname: Meinkoth
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics / Q000502:physiology; D005434:Flow Cytometry; D051381:Rats; D013961:Thyroid Gland / Q000166:cytology*; D018631:ras Proteins / Q000502:physiology*
chemical_list: D019938:Cyclin D1; D018631:ras Proteins; D001973:Bromodeoxyuridine