TY - JOUR
T1 - A novel crosstalk between calcium/calmodulin kinases II and IV regulates cell proliferation in myeloid leukemia cells
AU - Monaco, Sara
AU - Rusciano, Maria Rosaria
AU - Maione, Angela S.
AU - Soprano, Maria
AU - Gomathinayagam, Rohini
AU - Todd, Lance R.
AU - Campiglia, Pietro
AU - Salzano, Salvatore
AU - Pastore, Lucio
AU - Leggiero, Eleonora
AU - Wilkerson, Donald C.
AU - Rocco, Monia
AU - Selleri, Carmine
AU - Iaccarino, Guido
AU - Sankar, Uma
AU - Illario, Maddalena
PY - 2015/2/1
Y1 - 2015/2/1
N2 - 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 G0/G1cell cycle arrest, impairing cell proliferation. Furthermore, U937 cells expressing CaMKIV show elevated levels of Cdk inhibitors p27kip1 and p16ink4a 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.
AB - 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 G0/G1cell cycle arrest, impairing cell proliferation. Furthermore, U937 cells expressing CaMKIV show elevated levels of Cdk inhibitors p27kip1 and p16ink4a 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.
KW - Calcium
KW - CaMK
KW - Cell cycle
KW - Proliferation
UR - http://www.scopus.com/inward/record.url?scp=84920068495&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84920068495&partnerID=8YFLogxK
U2 - 10.1016/j.cellsig.2014.11.007
DO - 10.1016/j.cellsig.2014.11.007
M3 - Article
C2 - 25446257
AN - SCOPUS:84920068495
VL - 27
SP - 204
EP - 214
JO - Cellular Signalling
JF - Cellular Signalling
SN - 0898-6568
IS - 2
ER -