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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 Calpha.

Abstract：

: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. PKCalpha 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, PKCalpha 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 PKCalpha subcellular distribution, these data implicate a role for ceramide in mediating the rapid postirradiation translocation and inhibition of PKCalpha 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 PKCalpha and increased expression of Bcl-2 after gamma irradiation determine survival in TF-1 cells rescued from apoptosis with GM-CSF and that PKCalpha plays a role in mediating signals involved in sensing cellular damage and/or regulation of cell damage repair.

journal_name

Blood

journal_title

Blood

authors

Kelly ML,Tang Y,Rosensweig N,Clejan S,Beckman BS

subject

Has Abstract

pub_date

1998-07-15 00:00:00

pages

416-24

issue

eissn

0006-4971

issn

1528-0020

journal_volume

pub_type

杂志文章

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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 Calpha.