CaMKII regulates retinoic acid receptor transcriptional activity and the differentiation of myeloid leukemia cells
| Autor: | Jutong Si, LeMoyne Mueller, Steven J. Collins |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Myeloid
Receptors Retinoic Acid Cellular differentiation Retinoic acid HL-60 Cells Tretinoin Biology chemistry.chemical_compound Leukemia Promyelocytic Acute Myeloid Cell Differentiation hemic and lymphatic diseases medicine Humans Promoter Regions Genetic CAMK Myeloid leukemia Cell Differentiation General Medicine Enzyme Activation Gene Expression Regulation Neoplastic Retinoic acid receptor medicine.anatomical_structure chemistry Calcium-Calmodulin-Dependent Protein Kinases Cancer research Calcium-Calmodulin-Dependent Protein Kinase Type 2 Signal Transduction Research Article medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 117:1412-1421 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci30779 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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