GSK-3 promotes conditional association of CREB and its coactivators with MEIS1 to facilitate HOX-mediated transcription and oncogenesis.
Cancer Cell, 2010/6/15;17(6):597-608.
Wang Z[1], Iwasaki M, Ficara F, Lin C, Matheny C, Wong SH, Smith KS, Cleary ML
Affiliations
PMID: 20541704DOI: 10.1016/j.ccr.2010.04.024
Impact factor: 38.585
Abstract
Acute leukemias induced by MLL chimeric oncoproteins are among the subset of cancers distinguished by a paradoxical dependence on GSK-3 kinase activity for sustained proliferation. We demonstrate here that GSK-3 maintains the MLL leukemia stem cell transcriptional program by promoting the conditional association of CREB and its coactivators TORC and CBP with homedomain protein MEIS1, a critical component of the MLL-subordinate program, which in turn facilitates HOX-mediated transcription and transformation. This mechanism also applies to hematopoietic cells transformed by other HOX genes, including CDX2, which is highly expressed in a majority of acute myeloid leukemias, thus providing a molecular approach based on GSK-3 inhibitory strategies to target HOX-associated transcription in a broad spectrum of leukemias.
MeSH terms
Animals; CREB-Binding Protein; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Cyclic AMP Response Element-Binding Protein; DNA-Binding Proteins; Down-Regulation; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Glycogen Synthase Kinase 3; Homeodomain Proteins; Humans; Indoles; Leukemia, Myeloid, Acute; Maleimides; Mice; Mice, Inbred C57BL; Models, Biological; Myeloid Ecotropic Viral Integration Site 1 Protein; Myeloid-Lymphoid Leukemia Protein; Neoplasm Proteins; Neoplastic Stem Cells; Oncogene Proteins, Fusion; Phosphorylation; Pre-B-Cell Leukemia Transcription Factor 1; Protein Binding; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-fos; Signal Transduction; Transcription Factors; Transcription, Genetic
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