Re-expression of senescent markers in deinduced reversibly immortalized cells.
We have developed a simian virus 40 (SV40) T-antigen immortalized human cell line, 1MR90-D305.2H4 (IDH4), in which the expression of T-antigen is controlled by the mouse mammary tumor virus (MMTV) promoter and thus regulated by steroids such as dexamethasone. Studies on the regulation of proliferation by T-antigen led to the formulation of a two-stage model for human cell immortalization, in which a mortality stage 1 mechanism (M1) was the target of T-antigen action, and an independent mortality stage 2 mechanism (M2) produced crisis and prevented T-antigen from directly immortalizing cells. Rarely, a cell expressing T-antigen escaped crisis (e.g., M2) and was capable of indefinite proliferation. This model predicted that the deinduction of T-antigen in IDH4 cells would lead to the reexpression of the M1 mechanism, and thus a reexpression of the senescent phenotype. Our study confirms the prediction that, in the absence of steroids, IDH4 cells express a variety of morphological and biochemical markers characteristic of normal senescent human fibroblasts.
Shay
J W
JW
University of Texas Southwestern Medical Center, Department of Cell Biology and Neuroscience, Dallas 75235-9039.
West
M D
MD
Wright
W E
WE
D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D002455:Cell Division; D002461:Cell Line, Transformed; D016922:Cellular Senescence / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D015870:Gene Expression; D006801:Humans; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D008969:Molecular Sequence Data; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D013539:Simian virus 40
D000957:Antigens, Viral, Tumor; D017395:Plasminogen Activator Inhibitor 1; D003907:Dexamethasone; D004247:DNA