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

作者：Monaco Sara; Rusciano Maria Rosaria; Maione Angela S; Soprano Maria; Gomathinayagam Rohini; Todd Lance R; Campiglia Pietro; Salzano Salvatore; Pastore Lucio; Leggiero Eleonora; Wilkerson Donald C; Rocco Monia; Selleri Carmine; Iaccarino Guido; Sankar Uma^*; Illario Maddalena

来源：Cellular Signalling, 2015, 27(2): 204-214.

DOI：10.1016/j.cellsig.2014.11.007

• CaMK
• Proliferation
• Calcium
• Cell cycle

CaMKs link transient increases in intracellular Ca2+ 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 G(0)/G(1)cell 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, B-1 and D-1.
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.

• 出版日期2015-2