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Blood, 1 September 2000, Vol. 96, No. 5, pp. 1756-1763
HEMATOPOIESIS
Apoptosis is rapidly triggered by antisense depletion of
MCL-1 in differentiating U937 cells
Dale A. Moulding,
Richard
V. Giles,
David G. Spiller,
Michael R. H. White,
David M. Tidd, and
Steven W. Edwards
From the School of Biological Sciences and the
Department of Haematology, University of Liverpool, Liverpool, England.
Mcl-1 is a member of the Bcl-2 protein family, which has
been shown to delay apoptosis in transfection and/or overexpression experiments. As yet no gene knockout mice have been engineered, and so
there is little evidence to show that loss of Mcl-1 expression is
sufficient to trigger apoptosis. U937 cells constitutively express the
antiapoptotic protein Bcl-2; but during differentiation, in response to
the phorbol ester PMA (phorbol 12  -myristate 13  -acetate), Mcl-1
is transiently induced. The purpose of this investigation was to
determine the functional role played by Mcl-1 in this differentiation
program. Mcl-1 expression was specifically disrupted by chimeric
methylphosphonate/phosphodiester antisense oligodeoxynucleotides to
just 5% of control levels. The depletion of Mcl-1 messenger RNA (mRNA)
and protein was both rapid and specific, as indicated by the use of
control oligodeoxynucleotides and analysis of the expression of other
BCL2 family members and PMA-induced tumor necrosis
factor- (TNF-). Specific depletion of Mcl-1 mRNA and protein, in
the absence of changes in cellular levels of Bcl-2, results in a rapid
entry into apoptosis. Levels of the proapoptotic protein Bax remained
unchanged during differentiation, while Bak expression doubled within
24 hours. Apoptosis was detected within 4 hours of Mcl-1 antisense
treatment by a variety of parameters including a novel live cell
imaging technique allowing correlation of antisense treatment and
apoptosis in individual cells. The induction of Mcl-1 is required to
prevent apoptosis during differentiation of U937 cells, and the
constitutive expression of Bcl-2 is unable to compensate for the loss
of Mcl-1.
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