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(Received for publication, December 5, 1995, and in revised form, April 1, 1996)
From the Regional Research Laboratory, Kaiser Foundation Hospitals,
Los Angeles, California 90027
Anti-IgM treatment of Burkitt's lymphoma cells
is followed by either growth arrest or induction of apoptosis. In this
study we have explored the role of c-myc in these events.
Our results in Ramos cells indicate the following. (a) The
decline in c-myc mRNA occurs at about 4 h;
inhibition of about 80% being observed. (b) The stability
of c-myc message is involved since the half-life of
c-myc mRNA is decreased from about 30 min in untreated
cells to about 15 min following treatment with anti-IgM. In the
presence of cycloheximide, a protein synthesis inhibitor, the half-life
is increased to about 50 min and was unaltered by treatment with
anti-IgM. (c) By contrast, nuclear run-on experiments
indicated no change in transcription rates for c-myc
message due to treatment with anti-IgM. (d) A decrease in
c-myc causes apoptosis since specific repression of
c-myc with antisense oligonucleotides decreases the levels
of c-Myc, inhibits growth rate, decreases viability, and induces
apoptosis. (e) Anti-CD40 inhibition of apoptosis occurs
without alteration in anti-IgM-induced down-regulation of
c-myc mRNA, suggesting that it acts distally to
c-myc down-regulation. Other cell lines were also
investigated. In Epstein-Barr virus (EBV)-positive cell lines (Daudi,
Raji, and Namalwa), anti-IgM treatment for 24 h results in growth
inhibition without induction of apoptosis. In EBV-negative cell lines
(ST486 and CA46, as well as Ramos), a more heterogeneous pattern of
responses to anti-IgM are observed. Ramos and ST486 cells both show
growth inhibition and apoptosis upon anti-IgM treatment; CA46 cells
shown only growth inhibition but not apoptosis. Anti-IgM causes a
decline in c-myc mRNA levels in all of these lines, as
well as in c-Myc protein level in the two lines investigated, Daudi and
Ramos, regardless of apoptosis. Addition of antisense c-myc
oligonucleotides to the cells reduced growth in both Daudi and Ramos
cells lines, however it resulted in substantial apoptosis only in Ramos
cells.
These results suggest that anti-IgM destabilizes c-myc
mRNA by a process that involves mRNA turnover, rather than
transcription rates. However anti-IgM exerts differential effects in
EBV-positive and EBV-negative cell lines. EBV-positive cells are
uniformly resistant to apoptosis, while EBV-negative cell lines show a
tendency to apoptosis but with exceptions. Growth inhibition can be
uncoupled from apoptosis in EBV-positive cell lines, but not in those
EBV-negative cell lines prone to apoptosis. Furthermore,
down-regulation of c-myc message correlates with growth
inhibition in these cells, but is an insufficient link to apoptosis. By
contrast inhibition of apoptosis by anti-CD40 occurs even though
c-myc mRNA is decreased.
Volume 271, Number 31,
Issue of August 2, 1996
pp. 18875-18884
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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