p38-mediated Regulation of an Fas-associated Death Domain Protein-independent Pathway Leading to Caspase-8 Activation during TGFβ-induced Apoptosis in Human Burkitt Lymphoma B Cells BL41

• Published in: Molecular biology of the cell Vol. 12; no. 10; pp. 3139 - 3151
• Main Authors: Schrantz, Nicolas, Bourgeade, Marie-Françoise, Mouhamad, Shahul, Leca, Gérald, Sharma, Surendra, Vazquez, Aimé
• Format: Journal Article
• Language: English
• Published: The American Society for Cell Biology 01.10.2001
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.12.10.3139

On binding to its receptor, transforming growth factor β (TGFβ) induces apoptosis in a variety of cells, including human B lymphocytes. We have previously reported that TGFβ-mediated apoptosis is caspase-dependent and associated with activation of caspase-3. We show here that caspase-8 inhibitors strongly decrease TGFβ-mediated apoptosis in BL41 Burkitt's lymphoma cells. These inhibitors act upstream of the mitochondria because they inhibited the loss of mitochondrial membrane potential observed in TGFβ-treated cells. TGFβ induced caspase-8 activation in these cells as shown by the cleavage of specific substrates, including Bid, and the appearance of cleaved fragments of caspase-8. Our data show that TGFβ induces an apoptotic pathway involving sequential caspase-8 activation, loss of mitochondrial membrane potential, and caspase-9 and -3 activation. Caspase-8 activation was Fas-associated death domain protein (FADD)-independent because cells expressing a dominant negative mutant of FADD were still sensitive to TGFβ-induced caspase-8 activation and apoptosis. This FADD-independent pathway of caspase-8 activation is regulated by p38. Indeed, TGFβ-induced activation of p38 and two different inhibitors specific for this mitogen-activated protein kinase pathway (SB203580 and PD169316) prevented TGFβ-mediated caspase-8 activation as well as the loss of mitochondrial membrane potential and apoptosis. Overall, our data show that p38 activation by TGFβ induced an apoptotic pathway via FADD-independent activation of caspase-8.