Open Access

ARTICLE

TNF triggers mitogenic signals in NIH 3T3 cells but induces apoptosis when the cell cycle is blocked

René Rodríguez¹, Victor M. Campa¹, José Riera¹, M. Teresa Carcedo¹, David S. Ucker², Sofía Ramos¹, Pedro S. Lazo¹

1 Instituto Universitario de Oncología del Principado de Asturias and Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, 33071 Oviedo, Spain
2 Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, IL 60612, USA

* Corresponding Author: P.S. Lazo,

European Cytokine Network 2007, 18(4), 172-180. https://doi.org/10.1684/ecn.2007.0106

Accepted 29 October 2007;

Abstract

Tumor necrosis factor (TNF) is known to be a mediator of a variety of cellular responses including apoptotic death or proliferation depending on the target cell and the environmental conditions. We show here that TNF triggers both growth and death signals in NIH 3T3 murine fibroblasts. In cells arrested in G₀ by serum deprivation, TNF drives approximately 50% of them to enter the cell cycle, but kills the cells that remain quiescent. The presence of serum prevents toxic effects of TNF, suggesting that TNF can cooperate to drive cells through the cell cycle, but is unable to do so by itself and alternatively it triggers death signals in cells unable to proliferate. Interestingly, TNF induces a similar toxic effect in cells forced to stay at the G₀₁ /S border, S or M phases. We have explored the TNF apoptotic pathway in arrested cells. This mechanism is not due to the loss of the anti-apoptotic capacity of NFκB and is mediated by mitochondria since Bcl-2 overexpression partially inhibits cell death. There are, however, interesting differences in the kinetics of mitochondrial events which indicate that this form of sensitization to TNF leads to an apoptotic mechanism different from that observed after sensitization by RNA synthesis inhibition.

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