RETRACTED: The retinoic acid receptor/CaMKII interaction: Pharmacologic inhibition of CaMKII enhances the differentiation of myeloid leukemia cells
| Autor: | Jutong Si, Steven J. Collins, Julian A. Simon, Aaron D. Schuler, LeMoyne Mueller |
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| Rok vydání: | 2007 |
| Předmět: |
Receptors
Retinoic Acid Transplantation Heterologous HL-60 Cells Tretinoin Pharmacology Mice 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine Ca2+/calmodulin-dependent protein kinase Animals Humans Medicine Myeloid Cells Enzyme Inhibitors Phosphorylation Promoter Regions Genetic Molecular Biology business.industry Retinoic Acid Receptor alpha Myeloid leukemia Cell Differentiation Cell Biology Hematology Retinoic acid receptor Molecular Medicine Calcium-Calmodulin-Dependent Protein Kinase Type 2 business Neoplasm Transplantation |
| Zdroj: | Blood Cells, Molecules, and Diseases. 39:307-315 |
| ISSN: | 1079-9796 |
| DOI: | 10.1016/j.bcmd.2007.05.009 |
| Popis: | Certain myeloid leukemia cells, particularly the acute promyelocytic leukemia (APL) subset, undergo terminal granulocytic differentiation in response to retinoic acid (RA). RA mediates its biologic effects through specific retinoic acid receptors (RARs) which serve as ligand-activated nuclear transcription factors. The Ca(++)/calmodulin-dependent protein kinases (CaMKs) are multifunctional serine/threonine kinases that are regulated by Ca(++) signaling. We have observed significant cross-talk between these Ca(++) and RA signaling pathways that regulates the differentiation of myeloid leukemia cells. We observe that CaMKIIgamma is the CaMK that is predominantly expressed in myeloid cells. This enzyme localizes to the promoter of RAR target genes, physically interacts with and phosphorylates RARalpha and inhibits RAR transcriptional activity. KN-62, a pharmacological inhibitor of the CaMKs, enhances both retinoic acid receptor transcriptional activity as well as the terminal in vitro differentiation of certain myeloid leukemia cell lines including HL-60. However, this compound, as well as related synthetic analogs that enhance HL-60 terminal differentiation, fails to inhibit the growth of HL-60 xenografts in NOD-SCID mice likely because of the unfavorable pharmacokinetics displayed by these compounds. Nevertheless, our observations suggest that CaMKIIgamma may provide a new therapeutic target for the treatment of the RA-responsive human myeloid leukemias. |
| Databáze: | OpenAIRE |
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