Open AccessStimulation of CD30 in anaplastic large cell lymphoma leads to production of nuclear factor‐κB p52, which is associated with hyperphosphorylated Bcl‐3
Author(s) -
Nishikori Momoko,
Ohno Hitoshi,
Haga Hironori,
Uchiyama Takashi
Publication year - 2005
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2005.00078.x
Subject(s) - anaplastic large cell lymphoma , transactivation , cd30 , apoptosis , stimulation , chemistry , microbiology and biotechnology , cancer research , colocalization , downregulation and upregulation , signal transduction , biology , lymphoma , gene expression , endocrinology , biochemistry , gene , immunology , tumor cells
Anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL) express CD30 at high levels, but stimulation of this molecule has been reported to induce contradictory effects. To elucidate the molecular mechanism of CD30‐mediated apoptosis of ALCL, we compared the gene expression profiles of t(2;5)(p23;q35)‐positive ALCL with those of HL altered by CD30 agonistic stimulation. The results showed that BCL3 , the high‐level expression of which in ALCL was previously reported, was further upregulated in response to CD30 stimulation, along with several pro‐apoptotic genes. Bcl‐3 protein was present as an intermediate phospho‐form in the resting‐state ALCL, becoming hyperphosphorylated (Bcl‐3 P ) upon stimulation. We next found that the stimulation promoted de novo synthesis of the nuclear factor (NF)‐κB2/p100 precursor as well as processing to p52, and a series of immunoprecipitation and western blotting analyses consistently showed association of Bcl‐3 P with p52 in CD30‐stimulated ALCL. An electrophoretic mobility shift assay revealed the induction of κB binding activity of the p52 homodimer, and nuclear colocalization of Bcl‐3 and p52 was demonstrated in anaplastic lymphoma kinase‐positive ALCL tumor tissues by immunohistochemistry. As Bcl‐3 can act as an antirepressor or transactivator or both, we propose that the (p52) 2 /Bcl‐3 P ternary complex, which is specifically induced in CD30‐stimulated ALCL, can modulate expression of apoptosis‐related genes regulated by NF‐κB, thereby accounting for CD30‐mediated apoptosis of ALCL. ( Cancer Sci 2005; 96: 487–497)