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

N. Schrantz, M. F. Bourgeade, S. Mouhamad, G. Leca, S. Sharma, A. Vazquez

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3139-3151
Number of pages13
JournalMolecular Biology of the Cell
Volume12
Issue number10
DOIs
StatePublished - 2001
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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