Activated Ca2+/calmodulin-dependent protein kinase IIgamma is a critical regulator of myeloid leukemia cell proliferation.
Ca(2+) signaling is an important component of signal transduction pathways regulating B and T lymphocyte proliferation, but the functional role of Ca(2+) signaling in regulating myeloid leukemia cell proliferation has been largely unexplored. We observe that the activated (autophosphorylated) Ca(2+)/calmodulin-dependent protein kinase IIgamma (CaMKIIgamma) is invariably present in myeloid leukemia cell lines as well as in the majority of primary acute myelogenous leukemia patient samples. In contrast, myeloid leukemia cells induced to terminally differentiate or undergo growth arrest display a marked reduction in this CaMKIIgamma autophosphorylation. In cells harboring the bcr-abl oncogene, the activation (autophosphorylation) of CaMKIIgamma is regulated by this oncogene. Moreover, inhibition of CaMKIIgamma activity with pharmacologic agents, dominant-negative constructs, or short hairpin RNAs inhibits the proliferation of myeloid leukemia cells, and this is associated with the inactivation/down-regulation of multiple critical signal transduction networks involving the mitogen-activated protein kinase, Janus-activated kinase/signal transducers and activators of transcription (Jak/Stat), and glycogen synthase kinase (GSK3beta)/beta-catenin pathways. In myeloid leukemia cells, CaMKIIgamma directly phosphorylates Stat3 and enhances its transcriptional activity. Thus, CaMKIIgamma is a critical regulator of multiple signaling networks regulating the proliferation of myeloid leukemia cells. Inhibiting CaMKIIgamma may represent a novel approach in the targeted therapy of myeloid leukemia.
Si
Jutong
J
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Collins
Steven J
SJ
D018952:Antigens, CD34 / Q000096:biosynthesis; D017209:Apoptosis; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D015398:Signal Transduction
D018952:Antigens, CD34; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C517662:CAMK2G protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D038362:Glycogen Synthase Kinase 3