Ligation of CD40 rescues Ramos-Burkitt lymphoma B cells from calcium ionophore- and antigen receptor-triggered apoptosis by inhibiting activation of the cysteine protease CPP32/Yama and cleavage of its substrate PARP

FEBS Lett. 1996 May 20;386(2-3):115-22. doi: 10.1016/0014-5793(96)00427-9.


The new and growing family of interleukin-1beta-converting enzyme (ICE) cysteine proteases are now recognised to be major effectors of cellular death by apoptosis. Like other members of this family, the CPP32/Yama proform is activated by processing to its active heterodimeric enzyme or apopain when it likely contributes to the process of apoptosis by cleaving poly(ADP-ribose) polymerase (PARP) and thereby inhibiting much of its DNA repair activity. Apoptosis plays a fundamental role in the regulation of the immune system where it is involved in the selection of both T and B lymphocytes bearing antigen receptor (AgR) for non-self. Cells of the Ramos Epstein-Barr virus (EBV)-genome-negative Burkitt lymphoma (BL) B cell line (Ramos-BL) can be triggered into growth arrest and apoptosis by treating with the calcium ionophore ionomycin or by crosslinking their surface AgR with antibodies directed against immunoglobulin (Ig)M (anti-IgM). Ionomycin- and AgR-triggered growth arrest and apoptosis are arrested by signals transduced through the surface CD40 of Ramos-BL B cells. Both ionomycin and anti-IgM trigger activation of CPP32 and cleavage of PARP prior to the onset of apoptosis; this process is abrogated by treatment with anti-CD40 and is independent of Bcl-2 expression. A tripeptide inhibitor of ICE family cysteine proteases, Z-Val-Ala-Asp-fluoromethylketone (zVAD-fmk) inhibits ionomycin- and AgR-triggered CPP32 activation, PARP cleavage and apoptosis, but not growth arrest, in Ramos-BL B cells. Thus, in this report we demonstrate that in a physiological system, activation of endogenous members of the ICE family, including CPP32, and cleavage of the death substrate PARP act as major effectors of apoptotic death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Antibodies / immunology
  • Apoptosis / physiology*
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Burkitt Lymphoma
  • CD40 Antigens / immunology
  • CD40 Antigens / metabolism*
  • Calcium
  • Caspase 3
  • Caspases*
  • Cell Line
  • Child, Preschool
  • Cysteine Endopeptidases / drug effects
  • Cysteine Endopeptidases / metabolism*
  • Humans
  • Immunoglobulin M / immunology
  • Ionomycin / pharmacology
  • Ionophores / pharmacology
  • Male
  • Mice
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Protease Inhibitors / pharmacology
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Antigen, B-Cell / metabolism*
  • Sheep
  • Time Factors


  • Amino Acid Chloromethyl Ketones
  • Antibodies
  • CD40 Antigens
  • Immunoglobulin M
  • Ionophores
  • Protease Inhibitors
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Antigen, B-Cell
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • Ionomycin
  • Poly(ADP-ribose) Polymerases
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases
  • Cysteine Endopeptidases
  • Calcium