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Blood, 1 May 2002, Vol. 99, No. 9, pp. 3439-3448
RED CELLS
Erythrocyte survival is promoted by plasma and suppressed by a
Bak-derived BH3 peptide that interacts with membrane-associated
Bcl-XL
Melanie Walsh,
Robert J. Lutz,
Thomas G. Cotter, and
Rosemary O'Connor
From the Department of Biochemistry and
Biosciences Research Institute, National University of Ireland,
Cork; and Immunogen Inc, Cambridge, MA.
Erythrocytes have a defined lifespan in vivo, and the signals that
maintain their survival in circulation or trigger their death are
unknown. Here, we investigated the control of erythrocyte survival and
death in an in vitro culture system where erythrocytes survived for 10 days in serum-free medium in the presence or absence of bovine serum.
Death of the cells in culture was correlated with increased exposure of
phosphatidylserine and increased levels of intracellular calcium. Cell
death could be suppressed by supplementing the medium with human plasma
or serum, resulting in a doubling of the lifespan to 20 days. Freshly
isolated erythrocytes and cultured erythrocytes were both found to
express Bcl-XL and, to a lesser extent, Bak in membrane
protein extracts. Treatment of the cells with a Bak-derived BH3
peptide fused to the internalization sequence of the antennapedia
protein, which has previously been shown to enter cells by diffusion
and antagonize Bcl-XL, resulted in substantial cell death
in erythrocyte cultures. BH3-induced death was accompanied by an
immediate increase in accumulation of intracellular calcium and could
be suppressed by plasma, but not by the caspase inhibitor zVAD. A BH3
peptide mutated at amino acid 78 of full-length Bak required for
heterodimerization with Bcl-XL had no effect on
cell viability or calcium levels. We conclude that the BH3 peptide
accelerates erythrocyte death through antagonization of
Bcl-XL. The data suggest that erythrocyte survival is
promoted by survival factors in plasma and by membrane-associated
Bcl-XL.
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