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GSK-3 promotes conditional association of CREB and its coactivators with MEIS1 to facilitate HOX-mediated transcription and oncogenesis.

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.

Pubmed ID: 20541704

Authors

  • Wang Z
  • Iwasaki M
  • Ficara F
  • Lin C
  • Matheny C
  • Wong SH
  • Smith KS
  • Cleary ML

Journal

Cancer cell

Publication Data

June 15, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: CA116606
  • Agency: NCI NIH HHS, Id: R01 CA116606
  • Agency: NCI NIH HHS, Id: R01 CA116606-05
  • Agency: NCI NIH HHS, Id: T32 CA009151
  • Agency: NCI NIH HHS, Id: T32 CA009151-37
  • Agency: NCI NIH HHS, Id: T32 CA09151

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-Lymphoid Leukemia Protein
  • Neoplasm Proteins
  • Neoplastic Stem Cells
  • Oncogene Proteins, Fusion
  • Phosphorylation
  • Protein Binding
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-fos
  • Signal Transduction
  • Transcription Factors
  • Transcription, Genetic