TGF-β1 Suppresses Apoptosis Via Differential Regulation Of MAP Kinases And Ceramide Production

Serum deprivation induces apoptosis in NIH3T3 cells, which is associated with increased intracellular ceramide generation and with the activation of p38 mitogen-activated protein (MAP) kinase. Treatment of cells with transforming growth factor-β1 (TGF-β1) activated the extracellular signal regulated kinase 1 and 2 (ERK1/ERK2), inhibited the serum deprivation-induced p38 activation and the increase in intracellular ceramide formation, leading to the stimulation of cell proliferation and the suppression of apoptosis. Inhibition of p38 MAP kinase by SB203580 significantly reduced the serum deprivation-induced apoptosis. Over-expression of p38 increased the cell apoptosis and reduced the anti-apoptotic effect of TGF-β1. Inhibition of ERK1/ERK2 by PD98059 completely inhibited the TGF-β1-stimulated proliferation and partially inhibited the anti-apoptotic effects of TGF-β1. Neither SB203580 nor PD98059 has obvious effect on TGF-β1-mediated inhibition of the increased ceramide generation. Serum deprivation-induced apoptosis in NIH3T3 cells can also be blocked by broad-spectrum caspase inhibitor. TGF-β1 treatment has an inhibitory effect on caspase activities. Our results indicate that ceramide, p38, and ERK1/ERK2 play critical but differential roles in cell proliferation and stress-induced apoptosis. TGF-β1 suppresses the serum deprivation-inducedapoptosis via its distinct effects on complex signaling events involving the activation of ERK1/ERK2 and the inhibition of p38 activation and increased ceramide generation.