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Granulocyte-Macrophage Colony-Stimulating Factor Rescues TF-1
Leukemia Cells From Ionizing Radiation-Induced Apoptosis Through a
Pathway Mediated by Protein Kinase C
Mary L. Kelly,
Yan Tang,
Nitsa Rosensweig,
Sanda Clejan, and
Barbara S. Beckman
From the Interdisciplinary Program in Molecular and Cellular Biology,
Tulane University, New Orleans, LA; the Department of Pharmacology,
Tulane University School of Medicine, New Orleans, LA; and the
Department of Pathology and Laboratory Medicine, Tulane University
Medical Center, New Orleans, LA.
Protein kinase C (PKC) activity has a recognized role in mediating
apoptosis. However, the role of individual PKC isoforms in apoptosis is
poorly defined. Therefore, we investigated the translocation of
individual PKC isoforms during radiation-induced apoptosis with and
without rescue from apoptosis by granulocyte-macrophage colony-stimulating factor (GM-CSF) in the human erythroleukemia cell
line TF-1. PKC was translocated from the particulate to cytosolic
fraction of TF-1 cells within 5 minutes of treatment with
apoptosis-inducing levels of ionizing radiation. However, this
postirradiation translocation did not occur when cells were rescued
from apoptosis by GM-CSF. Furthermore, treatment of cells with Gö
6976, an inhibitor of classical PKC isoforms, abrogated the rescue
effect of GM-CSF. The calcium-independent novel PKC isoform, PKC
appeared to be degraded in both the particulate and cytosolic fractions
of TF-1 cells after treatment with apoptosis-inducing levels of
ionizing radiation in either the presence or absence of GM-CSF rescue.
Levels of ceramide, a lipid mediator of apoptosis, were measured at 2, 4, 8, 10, and 60 minutes after treatment with ionizing radiation and
were substantially reduced in TF-1 cells rescued from apoptosis by
GM-CSF compared with apoptotic TF-1 cells. The largest decrease in
ceramide production seen was at 4 minutes postirradiation, with a 46%
reduction in ceramide levels in TF-1 cells rescued from apoptosis by
GM-CSF compared with those in apoptotic TF-1 cells. Because ceramide
has been shown to affect PKC subcellular distribution, these data
implicate a role for ceramide in mediating the rapid postirradiation
translocation and inhibition of PKC in TF-1 cells not rescued from
apoptosis by GM-CSF. Expression of the antiapoptotic protein Bcl-2
doubled in TF-1 cells rescued from apoptosis by GM-CSF, but did not
increase in unrescued cells. Our findings suggest that activated PKC
and increased expression of Bcl-2 after  irradiation determine
survival in TF-1 cells rescued from apoptosis with GM-CSF and that
PKC plays a role in mediating signals involved in sensing cellular damage and/or regulation of cell damage repair.
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 416-424
© 1998 by the American Society of Hematology.
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