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Activated Ca++/calmodulin dependent protein kinase IIgamma is a critical regulator of myeloid leukemia cell proliferation

Si, Jutong and Collins, Steven J (2008) Activated Ca++/calmodulin dependent protein kinase IIgamma is a critical regulator of myeloid leukemia cell proliferation. Cancer Research, 68 (10). pp. 3733-3742. ISSN 1538-7445

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Ca++ signaling is an important component of signal transduction pathways regulating B and T lymphocyte proliferation, but the functional role of Ca++ signaling in regulating myeloid leukemia cell proliferation has been largely unexplored. We observe that the activated (autophosphorylated) Ca++/calmodulin-dependent protein kinase II (CaMKII) is invariably present in myeloid leukemia cell lines as well as in the majority of primary acute myelogenous leukemia (AML) patient samples. In contrast myeloid leukemia cells induced to terminally differentiate or undergo growth arrest display a marked reduction in this CaMKII autophosphorylation. In cells harboring the bcr-abl oncogene, the activation (autophosphorylation) of CaMKII is regulated by this oncogene. Moreover, inhibition of CaMKII activity with pharmacological agents, dominant negative constructs or shRNAs inhibits the proliferation of myeloid leukemia cells, and this is associated with the inactivation / downregulation of multiple critical signal transduction networks involving the MAP kinase, JAK/Stat and GSK3 / -catenin pathways. In myeloid leukemia cells CaMKII directly phosphorylates Stat3 and enhances its transcriptional activity. Thus CaMKII is a critical regulator of multiple signaling networks regulating the proliferation of myeloid leukemia cells. Inhibiting CaMKII may represent a novel approach in the targeted therapy of myeloid leukemia.

Item Type: Article or Abstract
Additional Information: The final published version is freely available at the journal website.
DOI: 10.1158/0008-5472.CAN-07-2509
PubMed ID: 18483256
PMCID: PMC2443690
Grant Numbers: R01 CA118971-01A1, R01 CA118971-02
Keywords or MeSH Headings: Antigens, CD34/biosynthesis Apoptosis Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism* Cell Differentiation Cell Line, Tumor Cell Proliferation Enzyme Activation Gene Expression Regulation, Enzymologic* Gene Expression Regulation, Leukemic* Glycogen Synthase Kinase 3/metabolism Humans K562 Cells Leukemia, Myeloid/metabolism Leukemia, Myeloid/pathology* Phosphorylation Signal Transduction Antigens, CD34 Glycogen Synthase Kinase 3 glycogen synthase kinase 3 beta CAMK2G protein, human Calcium-Calmodulin-Dependent Protein Kinase Type 2
Subjects: Cellular and Organismal Processes > Cell Physiology > Cell communication
Diseases > Hematologic and lymphatic diseases > Leukemia
Cellular and Organismal Processes > Cell Physiology > Cell proliferation
Depositing User: Library Staff
Date Deposited: 30 Jul 2008 18:00
Last Modified: 14 Feb 2012 14:42

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