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

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

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)204-214
Number of pages11
JournalCellular Signalling
Volume27
Issue number2
DOIs
StatePublished - Feb 1 2015

Fingerprint

Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases
Myeloid Leukemia
Myeloid Cells
Cell Proliferation
Calcium
Acute Myeloid Leukemia
Leukemia
abl Genes
Leukemia, Myelomonocytic, Acute
Leukemia, Monocytic, Acute
Cyclin B1
Biological Phenomena
Cyclin A
Cell Line
U937 Cells
K562 Cells
Cyclin D1
Growth
Up-Regulation

Keywords

  • Calcium
  • CaMK
  • Cell cycle
  • Proliferation

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

Cite this

Monaco, S., Rusciano, M. R., Maione, A. S., Soprano, M., Gomathinayagam, R., Todd, L. R., ... Illario, M. (2015). A novel crosstalk between calcium/calmodulin kinases II and IV regulates cell proliferation in myeloid leukemia cells. Cellular Signalling, 27(2), 204-214. https://doi.org/10.1016/j.cellsig.2014.11.007

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

In: Cellular Signalling, Vol. 27, No. 2, 01.02.2015, p. 204-214.

Research output: Contribution to journalArticle

Monaco, S, Rusciano, MR, Maione, AS, Soprano, M, Gomathinayagam, R, Todd, LR, Campiglia, P, Salzano, S, Pastore, L, Leggiero, E, Wilkerson, DC, Rocco, M, Selleri, C, Iaccarino, G, Sankar, U & Illario, M 2015, 'A novel crosstalk between calcium/calmodulin kinases II and IV regulates cell proliferation in myeloid leukemia cells', Cellular Signalling, vol. 27, no. 2, pp. 204-214. https://doi.org/10.1016/j.cellsig.2014.11.007
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. / A novel crosstalk between calcium/calmodulin kinases II and IV regulates cell proliferation in myeloid leukemia cells. In: Cellular Signalling. 2015 ; Vol. 27, No. 2. pp. 204-214.
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AU - Rusciano, Maria Rosaria

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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

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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.

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