CaMKII Regulates Retinoic Acid Receptor Transcriptional Activity and the Differentiation of Myeloid Leukemia Cells

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2007 Apr 14

PMID 17431504

Citations 26

Authors

Jutong Si

LeMoyne Mueller

Steven J Collins

Affiliations

Soon will be listed here.

Abstract

Retinoic acid receptors (RARs) are members of the nuclear hormone receptor family and regulate the proliferation and differentiation of multiple different cell types, including promyelocytic leukemia cells. Here we describe a biochemical/functional interaction between the Ca(2+)/calmodulin-dependent protein kinases (CaMKs) and RARs that modulates the differentiation of myeloid leukemia cells. We observe that CaMKIIgamma is the CaMK that is predominantly expressed in myeloid cells. CaMKII inhibits RAR transcriptional activity, and this enzyme directly interacts with RAR through a CaMKII LxxLL binding motif. CaMKIIgamma phosphorylates RARalpha both in vitro and in vivo, and this phosphorylation inhibits RARalpha activity by enhancing its interaction with transcriptional corepressors. In myeloid cell lines, CaMKIIgamma localizes to RAR target sites within myeloid gene promoters but dissociates from the promoter upon retinoic acid-induced myeloid cell differentiation. KN62, a pharmacological inhibitor of the CaMKs, enhances the terminal differentiation of myeloid leukemia cell lines, and this is associated with a reduction in activated (autophosphorylated) CaMKII in the terminally differentiating cells. These observations reveal a significant cross-talk between Ca(2+) and retinoic acid signaling pathways that regulates the differentiation of myeloid leukemia cells, and they suggest that CaMKIIgamma may provide a new therapeutic target for the treatment of certain human myeloid leukemias.

Citing Articles

miR-1 as a Key Epigenetic Regulator in Early Differentiation of Cardiac Sinoatrial Region.

Garcia-Padilla C, Lozano-Velasco E, Garcia-Lopez V, Aranega A, Franco D, Garcia-Martinez V Int J Mol Sci. 2024; 25(12).

PMID: 38928314 PMC: 11204236. DOI: 10.3390/ijms25126608.

Unveiling the role of CaMKII in retinal degeneration: from biological mechanism to therapeutic strategies.

Sun Y, Hao M, Wu H, Zhang C, Wei D, Li S Cell Biosci. 2024; 14(1):59.

PMID: 38725013 PMC: 11084033. DOI: 10.1186/s13578-024-01236-2.

Constitutively active CaMKII Drives B lineage acute lymphoblastic leukemia/lymphoma in tp53 mutant zebrafish.

Rothschild S, Lai G, Tombes R, Clements W PLoS Genet. 2023; 19(12):e1011102.

PMID: 38117861 PMC: 10766190. DOI: 10.1371/journal.pgen.1011102.

Synergistic Anticancer Effect of a Combination of Berbamine and Arcyriaflavin A against Glioblastoma Stem-like Cells.

Han J, Jung H Molecules. 2022; 27(22).

PMID: 36432068 PMC: 9699626. DOI: 10.3390/molecules27227968.

Put in a "Call" to Acute Myeloid Leukemia.

Lewuillon C, Laguillaumie M, Quesnel B, Idziorek T, Touil Y, Lemonnier L Cells. 2022; 11(3).

PMID: 35159351 PMC: 8834247. DOI: 10.3390/cells11030543.

References

Perissi V, Staszewski L, McInerney E, Kurokawa R, Krones A, Rose D . Molecular determinants of nuclear receptor-corepressor interaction. Genes Dev. 2000; 13(24):3198-208. PMC: 317209. DOI: 10.1101/gad.13.24.3198. View

Means A . Expression of a constitutive form of calcium/calmodulin dependent protein kinase II leads to arrest of the cell cycle in G2. EMBO J. 1992; 11(2):507-17. PMC: 556481. DOI: 10.1002/j.1460-2075.1992.tb05081.x. View

Means A . Regulatory cascades involving calmodulin-dependent protein kinases. Mol Endocrinol. 2000; 14(1):4-13. DOI: 10.1210/mend.14.1.0414. View

Glass C, Rosenfeld M . The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 2000; 14(2):121-41. View

Rachez C, Gamble M, Chang C, Atkins G, Lazar M, Freedman L . The DRIP complex and SRC-1/p160 coactivators share similar nuclear receptor binding determinants but constitute functionally distinct complexes. Mol Cell Biol. 2000; 20(8):2718-26. PMC: 85487. DOI: 10.1128/MCB.20.8.2718-2726.2000. View

Ren Y, Behre E, Ren Z, Zhang J, Wang Q, Fondell J . Specific structural motifs determine TRAP220 interactions with nuclear hormone receptors. Mol Cell Biol. 2000; 20(15):5433-46. PMC: 85995. DOI: 10.1128/MCB.20.15.5433-5446.2000. View

Lee S, Jung S, Kim Y, Na S, Lee Y, Lee J . Two distinct nuclear receptor-interaction domains and CREB-binding protein-dependent transactivation function of activating signal cointegrator-2. Mol Endocrinol. 2001; 15(2):241-54. DOI: 10.1210/mend.15.2.0595. View

Chang B, Mukherji S, Soderling T . Calcium/calmodulin-dependent protein kinase II inhibitor protein: localization of isoforms in rat brain. Neuroscience. 2001; 102(4):767-77. DOI: 10.1016/s0306-4522(00)00520-0. View

Hook S, Means A . Ca(2+)/CaM-dependent kinases: from activation to function. Annu Rev Pharmacol Toxicol. 2001; 41:471-505. DOI: 10.1146/annurev.pharmtox.41.1.471. View

10.

Anderson K, Means A . Defective signaling in a subpopulation of CD4(+) T cells in the absence of Ca(2+)/calmodulin-dependent protein kinase IV. Mol Cell Biol. 2001; 22(1):23-9. PMC: 134209. DOI: 10.1128/MCB.22.1.23-29.2002. View

11.

Tallman M, Nabhan C, Feusner J, Rowe J . Acute promyelocytic leukemia: evolving therapeutic strategies. Blood. 2002; 99(3):759-67. DOI: 10.1182/blood.v99.3.759. View

12.

Keriel A, Stary A, Sarasin A, Rochette-Egly C, Egly J . XPD mutations prevent TFIIH-dependent transactivation by nuclear receptors and phosphorylation of RARalpha. Cell. 2002; 109(1):125-35. DOI: 10.1016/s0092-8674(02)00692-x. View

13.

Lisman J, Schulman H, Cline H . The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci. 2002; 3(3):175-90. DOI: 10.1038/nrn753. View

14.

Si J, Collins S . IL-3-induced enhancement of retinoic acid receptor activity is mediated through Stat5, which physically associates with retinoic acid receptors in an IL-3-dependent manner. Blood. 2002; 100(13):4401-9. DOI: 10.1182/blood-2001-12-0374. View

15.

Kao H, Han C, Komar A, Evans R . Co-repressor release but not ligand binding is a prerequisite for transcription activation by human retinoid acid receptor alpha ligand-binding domain. J Biol Chem. 2002; 278(9):7366-73. DOI: 10.1074/jbc.M207569200. View

16.

Metivier R, Penot G, Hubner M, Reid G, Brand H, Kos M . Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell. 2003; 115(6):751-63. DOI: 10.1016/s0092-8674(03)00934-6. View

17.

Gaudilliere B, Konishi Y, de la Iglesia N, Yao G, Bonni A . A CaMKII-NeuroD signaling pathway specifies dendritic morphogenesis. Neuron. 2004; 41(2):229-41. DOI: 10.1016/s0896-6273(03)00841-9. View

18.

BREITMAN T, Selonick S, Collins S . Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc Natl Acad Sci U S A. 1980; 77(5):2936-40. PMC: 349521. DOI: 10.1073/pnas.77.5.2936. View

19.

Hashimoto Y, Soderling T . Calcium . calmodulin-dependent protein kinase II and calcium . phospholipid-dependent protein kinase activities in rat tissues assayed with a synthetic peptide. Arch Biochem Biophys. 1987; 252(2):418-25. DOI: 10.1016/0003-9861(87)90048-8. View

20.

Huang M, Ye Y, Chen S, Chai J, Lu J, Zhoa L . Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood. 1988; 72(2):567-72. View