Bcr-Abl reduces endoplasmic reticulum releasable calcium levels by a Bcl-2-independent mechanism and inhibits calcium-dependent apoptotic signaling.
The Bcr-Abl oncoprotein plays a major role in the development and progression of chronic myeloid leukemia (CML). Several studies have suggested that the expression levels of Bcr-Abl are elevated at disease progression to blast crisis and that this plays a significant role in the achievement of drug resistance. We have established cell lines expressing low and high levels of Bcr-Abl to study the molecular mechanisms involved in disease progression and drug resistance. It is now known that the endoplasmic reticulum (ER) can play a major role in the regulation of apoptosis. We therefore investigated whether Bcr-Abl expression modulates ER homeostasis and interferes with ER-mediated apoptotic pathways to promote survival. Bcr-Abl-expressing cells exhibit a decreased amount of free releasable calcium in the ER as well as a weaker capacitative calcium entry response, relative to parental cells. This effect is independent of Bcl-2, which is a known modulator of ER calcium homeostasis. The reduction in ER releasable calcium results in inhibition of the ER/mitochondria-coupling process and mitochondrial calcium uptake. This study demonstrates a novel downstream consequence of Bcr-Abl signaling. The ability to negate calcium-dependent apoptotic signaling is likely to be a major prosurvival mechanism in Bcr-Abl-expressing cells.
Department of Biochemistry, BioSciences Institute, University College Cork, Cork, Ireland.
Katarzyna
K
Piwocka
Susanne
S
Vejda
Thomas G
TG
Cotter
Gerald C
GC
O'Sullivan
Sharon L
SL
McKenna
D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D016044:Fusion Proteins, bcr-abl; D002118:Calcium