A novel crosstalk between calcium/calmodulin kinases II and IV regulates cell proliferation in myeloid leukemia cells.

Authors:
Sara Monaco
Sara Monaco
University of Pittsburgh Medical Center
United States
Maria Rosaria Rusciano
Maria Rosaria Rusciano
University of Naples Federico II
Italy
Maria Soprano
Maria Soprano
Federico II University
Napoli | Italy
Rohini Gomathinayagam
Rohini Gomathinayagam
University of Kentucky
United States
Lance R Todd
Lance R Todd
University of Louisville
United States
Pietro Campiglia
Pietro Campiglia
University of Salerno
Salvatore Salzano
Salvatore Salzano
Instituto di Endocrinologia ed Oncologia Sperimentale

Cell Signal 2015 Feb 15;27(2):204-14. Epub 2014 Nov 15.

Dipartimento di Scienze Mediche Traslazionali, Federico II University, Naples, Italy. Electronic address:

CaMKs link transient increases in intracellular Ca(2+) with biological processes. In myeloid leukemia cells, CaMKII, activated by the bcr-abl oncogene, promotes cell proliferation. Inhibition of CaMKII activity restricts cell proliferation, and correlates with growth arrest and differentiation. The mechanism by which the inhibition of CaMKII results in growth arrest and differentiation in myeloid leukemia cells is still unknown. We report that inhibition of CaMKII activity results in an upregulation of CaMKIV mRNA and protein in leukemia cell lines. Conversely, expression of CaMKIV inhibits autophosphorylation and activation of CaMKII, and elicits G0/G1cell cycle arrest,impairing cell proliferation. Furthermore, U937 cells expressing CaMKIV show elevated levels of Cdk inhibitors p27(kip1) and p16(ink4a) and reduced levels of cyclins A, B1 and D1. These findings were also confirmed in the K562 leukemic cell line. The relationship between CaMKII and CaMKIV is also observed in primary acute myeloid leukemia (AML) cells, and it correlates with their immunophenotypic profile. Indeed, immature MO/M1 AML showed increased CaMKIV expression and decreased pCaMKII, whereas highly differentiated M4/M5 AML showed decreased CaMKIV expression and increased pCaMKII levels. Our data reveal a novel cross-talk between CaMKII and CaMKIV and suggest that CaMKII suppresses the expression of CaMKIV to promote leukemia cell proliferation.

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http://dx.doi.org/10.1016/j.cellsig.2014.11.007DOI Listing

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February 2015
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